transforming-growth-factor-beta and Hypersensitivity

We found for the first time that IL-4 and IL-13, signature type 2 cytokines, are able to induce periostin expression. We and others have subsequently shown that periostin is highly expressed in chronic inflammatory diseases-asthma, atopic dermatitis, eosinophilc chronic sinusitis/chronic rhinosinusitis with nasal polyp, and allergic conjunctivitis-and that periostin plays important roles in the pathogenesis of these diseases. The epithelial/mesenchymal interaction via periostin is important for the onset of allergic inflammation, in which periostin derived from fibroblasts acts on epithelial cells or fibroblasts, activating their NF-κB. Moreover, the immune cell/non-immune cell interaction via periostin may be also involved. Now the significance of periostin has been expanded into other inflammatory or fibrotic diseases such as scleroderma and pulmonary fibrosis. The cross-talk of periostin with TGF-β or pro-inflammatory cytokines is important for the underlying mechanism of these diseases. Because of its pathogenic importance and broad expression, diagnostics or therapeutic drugs can be potentially developed to target periostin as a means of treating these diseases.

Topics: Anti-Inflammatory Agents; Cell Adhesion Molecules; Dermatitis, Atopic; Epithelial Cells; Fibroblasts; Gene Expression Regulation; Humans; Hypersensitivity; Inflammation; Interleukin-13; Interleukin-4; Mesenchymal Stem Cells; NF-kappa B; Signal Transduction; Transforming Growth Factor beta

The idea of regulatory T cells (Tregs) lost its popularity during the 1980s and 1990s, since immunologists failed to elucidate how the innate regulation of immunological reactions worked. The entire re-evaluation of the Tregs was supported due to the increasingly influential and state of the art immunological techniques, as cell sorting and also the expanding understanding of the immune system and its functions which aided in attaining a greater insight into the mechanisms of regulation and suppression. Many researchers nowadays have demonstrated that Tregs may well have therapeutic possibilities for the treatment of autoimmune diseases if it was a possibility to isolate and infuse these Tregs into patients, preferably without any harmful side effects. Therefore, modulation of Tregs as well as their generation is being researched since they were proposed as therapeutic interventions in several disease sceneries, nonetheless, sometimes with disastrous consequences. Consequently, a full and complete understanding of the exceptional biology of human Tregs is fundamental for the accurate interpretation of found data, before therapeutic interventions can be undertaken. This literature study gives an overview of the current accessible information on the topic of the characterization, the generation, regulation and functions of the Inducible Treg populations and their subsets in the human immune system.

Topics: Animals; Autoimmune Diseases; Cytokines; Forkhead Transcription Factors; Humans; Hypersensitivity; Immunity, Innate; Immunity, Mucosal; Immunologic Factors; Immunotherapy; Neoplasms; Phenotype; Signal Transduction; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Upon antigen-specific stimulation, naïve CD4⁺ T cells have the potential to differentiate into various T helper (Th) cell subsets. Earlier models of Th cell differentiation focused on IFN-γ-producing Th1 cells and IL-4-secreting Th2 cells. The discovery of additional CD4⁺ Th cell subsets has extended our understanding of Th cell differentiation beyond this dichotomy. Among these is the recently described Th9 cell subset, which preferentially produces interleukin (IL)-9. Here, we review the latest developments in Th9 cell development and differentiation, focusing on contributing environmental signals, and discuss potential physiological and pathophysiological functions of these cells. We describe the challenges inherent to unambiguously defining roles for Th9 cells using the available experimental animal models, and suggest new experimental models to address these concerns.

Topics: Adaptive Immunity; Animals; Humans; Hypersensitivity; Interferon Regulatory Factors; Interleukin-9; Mice; Models, Immunological; Neoplasms; Receptors, Antigen, T-Cell; Receptors, Interleukin-2; Receptors, Interleukin-4; Signal Transduction; T-Lymphocyte Subsets; T-Lymphocytes, Helper-Inducer; Transforming Growth Factor beta

Asthma markedly diminishes quality of life due to limited activity, absences from work or school and hospitalizations. Patients with severe asthma which are not controlled despite taking effective therapy are most in need of new treatment approaches. IL-13 was demonstrated as 'central mediator of allergic asthma'.. IL-13 has been implicated in the pathogenesis of asthma, idiopathic pulmonary fibrosis and COPD. IL-13 levels in the sputum and bronchial biopsy samples remain elevated in severe asthma despite the use of inhaled and systemic corticosteroids. Thus, IL-13 is a mediator involved in corticosteroid resistance. Periostin enhances profibrotic TGF-β signaling in subepithelial fibrosis associated with asthma. IL-13 induces bronchial epithelial cells to secrete periostin. Periostin may be a biomarker for Th2 induced airway inflammation. Lebrikizumab is a monoclonal antibody against IL-13. Lebrikizumab improved lung function in asthmatics who were symptomatic despite treatment with long acting beta agonist and inhaled corticosteroids and provided benefit in the treatment of severe uncontrolled asthma.. Lebrikizumab block IL-13 signaling through the IL-13Rα1/IL-4Rα receptor. There was a larger reduction in FENO in the high periostin subgroup than in the low periostin subgroup (34.4 vs 4.3%). Serum CCL17, CCL13 and total IgE levels decreased in the lebrikizumab group.

Topics: Adrenal Cortex Hormones; Animals; Antibodies, Monoclonal; Asthma; Biological Products; Biomarkers; Bronchi; Cell Adhesion Molecules; Eosinophils; Humans; Hypersensitivity; Inflammation; Interleukin-13; Interleukin-33; Interleukin-4; Interleukins; Lung; Nitric Oxide; Quality of Life; Transforming Growth Factor beta

This review discusses the current state of immunotherapy and how the CD4 T-cell response is pivotal in altering the allergic response.. PubMed literature review.. Articles pertaining to subcutaneous, sublingual, and oral immunotherapies, with specific emphasis on those describing the T-cell response.. Although many drugs are available that help ameliorate allergic symptoms, the only intervention that has proved to provide long-term benefit and modulation of disease is immunotherapy. Many routes of immunotherapy are being pursued, including subcutaneous, sublingual, and oral immunotherapies; however, subcutaneous immunotherapy has the historical record of leading to immune changes that alter the immune response at subsequent allergen exposure. These changes are mediated by the induction of peripherally derived T-regulatory cells and appear to occur only after high-dose therapy for 3 to 5 years. Newer methods of sublingual and oral immunotherapies are currently being investigated, but their efficacy is not yet on par with subcutaneous immunotherapy.. The primary cells ultimately responsible for successful immunomodulation are CD4 T cells, specifically peripherally derived T-regulatory cells.

Topics: CD4 Antigens; Desensitization, Immunologic; Humans; Hypersensitivity; Immunotherapy; Injections, Subcutaneous; Interleukin-10; Interleukin-2 Receptor alpha Subunit; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

The prevalence of allergic diseases has significantly increased in industrialized countries. Allergen-specific immunotherapy (AIT) remains as the only curative treatment. The knowledge about the mechanisms underlying healthy immune responses to allergens, the development of allergic reactions and restoration of appropriate immune responses to allergens has significantly improved over the last decades. It is now well-accepted that the generation and maintenance of functional allergen-specific regulatory T (Treg) cells and regulatory B (Breg) cells are essential for healthy immune responses to environmental proteins and successful AIT. Treg cells comprise different subsets of T cells with suppressive capacity, which control the development and maintenance of allergic diseases by various ways of action. Molecular mechanisms of generation of Treg cells, the identification of novel immunological organs, where this might occur in vivo, such as tonsils, and related epigenetic mechanisms are starting to be deciphered. The key role played by the suppressor cytokines interleukin (IL)-10 and transforming growth factor (TGF)-β produced by functional Treg cells during the generation of immune tolerance to allergens is now well established. Treg and Breg cells together have a role in suppression of IgE and induction of IgG4 isotype allergen-specific antibodies particularly mediated by IL-10. Other cell types such as subsets of dendritic cells, NK-T cells and natural killer cells producing high levels of IL-10 may also contribute to the generation of healthy immune responses to allergens. In conclusion, better understanding of the immune regulatory mechanisms operating at different stages of allergic diseases will significantly help the development of better diagnostic and predictive biomarkers and therapeutic interventions.

Topics: Allergens; Forkhead Transcription Factors; Humans; Hypersensitivity; Immune Tolerance; Interleukin-10; Models, Immunological; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

The transforming growth factor- β (TGF- β ) superfamily is a family of structurally related proteins that includes TGF- β , activins/inhibins, and bone morphogenic proteins (BMPs). Members of the TGF- β superfamily regulate cellular functions such as proliferation, apoptosis, differentiation, and migration and thus play key roles in organismal development. TGF- β is involved in several human diseases, including autoimmune disorders and vascular diseases. Activation of the TGF- β receptor induces phosphorylation of serine/threonine residues and triggers phosphorylation of intracellular effectors (Smads). Once activated, Smad proteins translocate to the nucleus and induce transcription of their target genes, regulating various processes and cellular functions. Recently, there has been an attempt to correlate the effect of TGF- β with various pathological entities such as allergic diseases and cancer, yielding a new area of research known as "allergooncology," which investigates the mechanisms by which allergic diseases may influence the progression of certain cancers. This knowledge could generate new therapeutic strategies aimed at correcting the pathologies in which TGF- β is involved. Here, we review recent studies that suggest an important role for TGF- β in both allergic disease and cancer progression.

Topics: Animals; Cell Transformation, Neoplastic; Humans; Hypersensitivity; Multigene Family; Neoplasms; Protein Binding; Protein Biosynthesis; Protein Isoforms; Protein Multimerization; Proteolysis; Receptors, Transforming Growth Factor beta; Signal Transduction; Smad Proteins; Transforming Growth Factor beta

Skin protects body from continual attack by microbial pathogens and environmental factors. Such barrier function of skin is achieved by multiple components including immune system, which is mainly regulated by lymphocytes. T lymphocytes (T cells) that express T cell receptor (TCR) α and β chains (αβT cells) control the strength and the type of immune response. CD4T cell population consists of helper T (Th) cell-subsets and immunosuppressive regulatory T (Treg) cells. Th1 cells produce IFN-γ and protect against intracellular pathogens. Th2 cells produce IL-4 family cytokines and participate in allergic skin diseases, including atopic dermatitis (AD). Th17 cells secrete IL-17, recruit granulocytes to fight against extracellular microorganisms, and play a role in psoriasis and AD. Th22 cells produce IL-22 that activates epithelial cells and mediates acanthosis in psoriasis and AD. On the other hand, Foxp3+ Treg cells attenuate immune responses partly via TGF-β or IL-10. Tissue resident memory T (Trm) cells in the skin-most of which are epidermal CD8T cells-constitute the first line of the defense against repeated infections. CD8 T cells are also engaged in psoriasis, lichen planus, and drug eruptions. Skin harbors innate-like αβT cells such as natural killer T (NKT) cells as well, whose function is not fully revealed. Understanding these αβT cells helps to comprehend skin diseases.

Topics: Animals; CD8-Positive T-Lymphocytes; Cell Differentiation; Cell Membrane; Cytokines; Dermatitis, Atopic; Drug Eruptions; Forkhead Transcription Factors; Humans; Hypersensitivity; Interleukin-10; Interleukin-17; Keratinocytes; Killer Cells, Natural; Lichen Planus; Mice; Phenotype; Skin; T-Lymphocytes; T-Lymphocytes, Helper-Inducer; Th1 Cells; Th2 Cells; Transforming Growth Factor beta

T(h)9 cells are a new subset of helper T cells, and the signature cytokine for T(h)9 cells is IL-9. Both T(h)9 cells and T(h)9 products are implicated in multiple disease settings. Thus, a clear understanding of how T(h)9 cells are induced and controlled is an important and clinically relevant issue. There are different molecular pathways identified thus far in the induction of T(h)9 cells, and activation of such diverse pathways requires integration of signals from TGF-β and IL-4 cytokine receptors as well as costimulatory molecules. These signals converge on the induction of multiple transcription factors that collectively drive the development of T(h)9 cells.

Topics: Animals; Bodily Secretions; Cell Differentiation; Humans; Hypersensitivity; Interleukin-9; Lymphocyte Activation; Mast Cells; Receptor Cross-Talk; Receptors, Interleukin-4; Signal Transduction; T-Lymphocytes, Helper-Inducer; Th2 Cells; Transforming Growth Factor beta

Allergen-specific immunotherapy (SIT) is the only available curative treatment of allergic diseases. Recent evidence provided a plausible explanation to its multiple mechanisms inducing both rapid desensitization and long-term allergen-specific immune tolerance, and suppression of allergic inflammation in the affected tissues. During SIT, peripheral tolerance is induced by the generation of allergen-specific regulatory T cells, which suppress proliferative and cytokine responses against the allergen of interest. Regulatory T cells are characterized by IL-10 and TGF-beta secretion and expression of important cell surface suppressive molecules such as cytotoxic T lymphocyte antigen-4 and programmed death-1 that directly or indirectly influence effector cells of allergic inflammation, such as mast cells, basophils and eosinophils. Regulatory T cells and particularly IL-10 also have an influence on B cells, suppressing IgE production and inducing the production of blocking type IgG4 antibodies. In addition, development of allergen-specific B regulatory cells that produce IL-10 and develop into IgG4 producing plasma cells represent essential players in peripheral tolerance. These findings together with the new biotechnological approaches create a platform for development of the advanced vaccines. Moreover, reliable biomarkers could be selected and validated with the intention to select the patients who will benefit most from this immune-modifying treatment. Thus, allergen-SIT could provide a complete cure for a larger number of allergic patients and novel preventive approaches need to be elaborated.

Topics: Allergens; B-Lymphocytes, Regulatory; Basophils; CTLA-4 Antigen; Desensitization, Immunologic; Eosinophils; Humans; Hypersensitivity; Immune Tolerance; Immunoglobulin E; Interleukin-10; Mast Cells; Programmed Cell Death 1 Receptor; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Vaccines

Successful allergen-specific immunotherapy (AIT) is associated with a marked decrease in symptoms on allergen exposure, a reduced requirement for 'rescue' anti-allergic drugs and improvement in patients' quality of life. These benefits persist for at least several years following discontinuation of immunotherapy - the hallmark of clinical and immunological tolerance. AIT has been shown to modulate both innate and adaptive immunological responses. Early suppression of innate effector cells of allergic inflammation (mast cells, basophils), regulation of pro-allergic T helper 2 type (Th 2) responses and IgE+ B cell responses have been shown to occur both in the tissue and in the peripheral blood during AIT. The allergen-tolerant state is associated with local and systemic induction of distinct populations of allergen-specific T regulatory cells including IL-10+ Tregs (Tr1 cells), TGF-β+ Tregs and FoxP3+ memory T regs. B cells are switched in favour of producing IgG (particularly IgG4) antibodies and associated blocking activity for IgE-dependent events, including basophil activation and IgE-facilitated allergen binding to B cells. An induction of IL-10+ B regulatory cells and alterations in dendritic cell subsets have also recently been described. These events are followed by the induction of T regulatory cells, suppression of allergen-specific T cell proliferation and immune deviation from Th2 in favour of Th1 responses. Alternative mechanisms of tolerance include apoptosis/deletion of antigen-specific memory Th2 cells and/or a failure of co-stimulation leading to T cell anergy.

Topics: Animals; Desensitization, Immunologic; Humans; Hypersensitivity; Immune Tolerance; Immunity, Innate; Immunoglobulin E; Immunosuppression Therapy; Interleukin-10; T-Lymphocytes, Regulatory; Th1-Th2 Balance; Transforming Growth Factor beta

Allergen-specific immunotherapy (SIT) is currently the best available curative treatment in allergies and has been used for the treatment of patients for the past 100 years. The formation of a Th2 cell predominant inflammation in addition to production of allergen-specific IgE, the attraction of proinflammatory cells and the degranulation of effector cells, such as mast cells, are essential mechanisms in allergy development. Tregs aim to diminish these effects by IL-10- and TGF-β-mediated anti-inflammatory reactions and therefore are one of the main targets in SIT. The induction of allergen tolerance is the key to successful SIT. With a special focus on Tregs, this review aims to clarify what is currently known about allergy development and the mode of action in allergen-SIT, which helps to develop further therapeutic strategies in the fight against allergic diseases.

Topics: Allergens; Animals; Desensitization, Immunologic; Humans; Hypersensitivity; Interleukin-10; Mice; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

The clinical and pathologic features of eosinophilic esophagitis (EE) include extensive tissue remodeling. Increasing evidence supports a key role for the eosinophil in multiple aspects of the esophageal remodeling and fibrosis seen in this allergic disease. This article reviews the clinical implications of esophageal remodeling and fibrosis in EE and discusses the possible pathogenic mechanisms inducing and regulating these responses. The focus is specifically on eosinophil and cytokine interactions with the esophageal epithelium, vascular endothelium, resident fibroblasts, and smooth muscle. Current and potential therapeutic interventions are discussed that may impact the development or resolution of chronic esophageal remodeling and fibrosis in EE.

Topics: Animals; Cell Communication; Cell Movement; Cell Survival; Chemotactic Factors, Eosinophil; Endothelial Cells; Eosinophilia; Eosinophils; Esophagitis; Fibroblasts; Fibrosis; Humans; Hypersensitivity; Inflammation; Intestinal Mucosa; Nerve Growth Factors; Transforming Growth Factor beta

Various populations of regulatory T (Treg) cells have been shown to play a central role in the maintenance of peripheral homeostasis and the establishment of controlled immune responses. Their identification as key regulators of immunologic processes in peripheral tolerance to allergens has opened an important era in the prevention and treatment of allergic diseases. Both naturally occurring CD4+CD25+ Treg cells and inducible populations of allergen-specific, IL-10-secreting Treg type 1 (T(R)1) cells inhibit allergen-specific effector cells in experimental models. Skewing of allergen-specific effector T cells to a regulatory phenotype appears to be a key event in the development of healthy immune response to allergens and successful outcome in allergen-specific immunotherapy. Forkhead box protein 3-positive CD4+CD25+ Treg cells and T(R)1 cells contribute to the control of allergen-specific immune responses in several major ways, which can be summarized as suppression of dendritic cells that support the generation of effector T cells; suppression of effector T(H)1, T(H)2, and T(H)17 cells; suppression of allergen-specific IgE and induction of IgG4; suppression of mast cells, basophils, and eosinophils; interaction with resident tissue cells and remodeling; and suppression of effector T-cell migration to tissues. Current strategies for drug development and allergen-specific immunotherapy exploit these observations, with the potential for preventive therapies and cure for allergic diseases.

Topics: Allergens; Animals; Desensitization, Immunologic; Humans; Hypersensitivity; Interleukin-10; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

The interaction of environmental and genetic factors with the immune system can lead to the development of allergic diseases. The essential step in this progress is the generation of allergen-specific CD4(+) T-helper (Th) type 2 cells that mediate several effector functions. The influence of Th2 cytokines leads to the production of allergen-specific IgE antibodies by B cells, development and recruitment of eosinophils, mucus production and bronchial hyperreactivity, as well as tissue homing of other Th2 cells and eosinophils. Meanwhile, Th1 cells may contribute to chronicity and the effector phases. T cells termed T regulatory (Treg) cells, which have immunosuppressive functions and cytokine profiles distinct from that of either Th1 or Th2 cells, have been intensely investigated during the last 13 years. Treg cell response is characterized by an abolished allergen-specific T cell proliferation and the suppressed secretion of Th1 and Th2-type cytokines. Treg cells are able to inhibit the development of allergen-specific Th2 and Th1 cell responses and therefore play an important role in a healthy immune response to allergens. In addition, Treg cells potently suppress IgE production and directly or indirectly suppress the activity of effector cells of allergic inflammation, such as eosinophils, basophils and mast cells. Currently, Treg cells represent an exciting area of research, where understanding the mechanisms of peripheral tolerance to allergens may soon lead to more rational and safer approaches for the prevention and cure of allergic diseases.

Topics: Allergens; Animals; Antigen Presentation; Dendritic Cells; Forkhead Transcription Factors; Humans; Hypersensitivity; Immune Tolerance; Immunoglobulin E; Immunotherapy; Interleukin-10; T-Lymphocytes, Regulatory; Th1 Cells; Th2 Cells; Transforming Growth Factor beta

During the past few years there has been significant pro - gress in understanding the mechanisms by which abnormal T-cell responses are generated in allergic diseases. Peripheral T-cell tolerance to environmental antigens is crucial for a healthy immune response and avoidance of allergy. The balance between T-helper (Th)2 cells and T-regulatory (Treg) cells has a critical role in the generation of immune responses to environmental antigens. Allergic individuals display an aberrant activation and expansion of Th2 cells. It appears that aberrant activation of Th2 cells in allergy is secondary to impaired mechanisms of peripheral T-cell tolerance that is normally mediated by antigen-specific T-cell anergy, Treg cells and suppressive cytokines, IL-10 and TGF-Beta. Therefore, a most appealing therapy for allergic diseases would be an allergen-specific immunotherapy that reduces Th2 cytokine production and promotes induction of anergy, Treg and suppressor cytokines. Such novel therapeutic approaches include the use of recombinant allergen-derived peptides, recombinant DNA technology and adjuvants. These approaches are employed individually or in combination in order to induce T-cell anergy and to utilize innate immunity in order to alter the balance of Th1- and Th2-type cytokines and generate or expand Treg in vivo.

Topics: Allergens; Animals; Cytokines; Desensitization, Immunologic; Humans; Hypersensitivity; Immune Tolerance; Oligonucleotides; Peptides; Receptor, Notch1; Signal Transduction; T-Lymphocytes, Regulatory; Th2 Cells; Thymic Stromal Lymphopoietin; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Vaccination; Vaccines, DNA

Topics: Antigen Presentation; Environment; Humans; Hygiene; Hypersensitivity; Immunoglobulin E; Interleukin-10; Th1 Cells; Th2 Cells; Transforming Growth Factor beta

Allergic diseases are caused by the induction of T helper (Th)2 cells and IgE responses specific for common environmental antigens (allergens) in susceptible individuals. There is increasing interest in the role of both naturally occurring and induced regulatory T cell (Treg) populations in preventing these inappropriate immune responses and the underlying sensitisation to allergens. Current evidence suggests that Tregs may actively prevent Th2 responses to allergens occurring in healthy non-atopic individuals and that their function may be impaired in allergic patients. Evidence that existing therapies may act by modulating Treg function is reviewed. Future research aims to understand the mechanisms involved in the generation and function of allergen-specific Tregs. A primary aim is to promote the development of optimised therapeutic regimens with the capacity to provide long-lasting, allergen-specific, inhibitory mechanisms at the time and site of allergen challenge.

Topics: Allergens; Animals; Asthma; Humans; Hypersensitivity; Hypersensitivity, Immediate; Immunotherapy; Inflammation; Interleukin-10; Models, Biological; T-Lymphocytes; T-Lymphocytes, Regulatory; Th2 Cells; Transforming Growth Factor beta

Allergy is an immunological disorder, which is driven by uncontrolled allergen-activated T cell subsets, leading to immediate type hypersensitivity against otherwise harmless environmental allergens. These allergens are tolerated by healthy individuals as well as by patients, who successfully underwent allergen-specific immunotherapy (SIT). The successful SIT is characterized by the induction of T cell unresponsiveness against the given allergen. Regulatory T cells (Tregs), which are installed or enhanced by SIT and govern the activity of potentially pro-allergic effector T cells, mediate this unresponsiveness. The current article reviews the mechanisms underlying the balance of these cell populations along with suppressive mechanisms of SIT, which may serve as future drug targets.

Topics: Allergens; Animals; Humans; Hypersensitivity; Immunotherapy; Interleukin-10; Transforming Growth Factor beta

The transforming growth factor beta (TGF-beta) plays a dual role in allergic disease. It is important in suppressing T cells and also mediates repair responses that lead to unwanted remodeling of tissues. Advances in the immunology of allergy indicate that allergens cause overreactions in the lymphocyte compartment because of the lack or decreased number of suppressive, regulatory T cells. TGF-beta was shown to induce regulatory T cells and participate directly in suppression of effector T cells. Therefore, TGF-beta may help return reactivity to allergens to normal subsymptomatic activity. Whether chronic inflammatory diseases such as asthma profit from TGF-beta-mediated suppression of specific immune responses or whether the TGF-beta-mediated tissue remodeling aggravates diseases more than it helps control immune reactions is unclear. This article addresses these issues and future strategies in this field.

Topics: Humans; Hypersensitivity; Inflammation; Transforming Growth Factor beta

Antigen-provoked polarization of CD4+ T cells along the Th1 pathway is often associated with autoimmune and chronic inflammatory diseases, whereas extreme skewing of the response toward a Th2 phenotype has been linked to atopy and allergic diseases. Intense interest in the underlying molecular mechanisms that control polarization has revealed a contingent of regulatory transcription factors, which not only help to define these pathways but also suggest potential sites for interventional tactics. Moreover, the recent identification of transcription factors specifically associated with CD4(+)CD25+ regulatory T-cells provides new clues regarding manipulation of this population in pursuit of directed immune regulation. Continued unraveling of the pathways underlying the development of deleterious immune responses and their control will guide new avenues of investigation and intervention.

Topics: Animals; Humans; Hypersensitivity; Immune System; Inflammation; T-Lymphocyte Subsets; Th2 Cells; Transcription Factors; Transforming Growth Factor beta

Th2 immune responses mediated by the secretion of IL-4, IL-5 and IL-13 are key in the pathogenesis of atopic disorders, including allergen-induced asthma, rhinoconjunctivitis and anaphylaxis. Although such responses are downregulated to some degree by conventional specific immunotherapy, this approach is only partially effective and has a substantial risk of adverse effects. Many strategies for immunotherapeutic prophylaxis and for treatment of atopic diseases have been devised on the basis of mouse allergy and autoimmune models, including the downregulation of Th2 responses by the induction of regulatory T cell activity, Th2 to Th1 immune deviation, Th1 crossregulation of Th2 immune responses, anergy and immunosuppressive cytokines. The blockade of events that are not allergen-specific, such as T cell costimulation and downstream events dependent on IgE, cytokines and chemokines, has also been pursued. With the exception of monoclonal antibody therapy for the blockade of IgE effector function, the application of most of these strategies to humans is at an early stage. Whether the inhibition of Th2 responses without concurrent downregulation of Th1 responses will be sufficient for allergic immunotherapy, particularly for atopic dermatitis and asthma, is an important but unresolved issue.

Topics: Animals; Chemokines; Cytokines; Humans; Hypersensitivity; Immunoglobulin E; Immunotherapy; Interleukin-10; Oligodeoxyribonucleotides; Th2 Cells; Transforming Growth Factor beta

Control of allergen-specific response by suppressive cytokines involves several layers of regulation, including secretion of the cytokine, deviation of cytokine expression by altered T-cell differentiation, immediate (de-) phosphorylation events upon binding of suppressive cytokines, and laterations in susceptibility of suppression.

Topics: Allergens; Animals; Cytokines; Humans; Hypersensitivity; T-Lymphocytes; Transforming Growth Factor beta

Senescence or biological aging impacts a vast variety of molecular and cellular processes. To date, it is unknown whether CD4(+) Th cells display an age-dependent bias for development into specific subpopulations. In this study, we show the appearance of a distinct CD4(+) T cell subset expressing IL-4 at an early stage of development in infant adenoids and cord blood that is lost during aging. We identified by flow cytometric, fluorescent microscopic, immunoblot, and mass spectrometric analysis a population of CD4(+) T cells that expressed an unglycosylated isoform of IL-4. This T cell subpopulation was found in neonatal but not in adult CD4(+) T cells. Furthermore, we show that the mRNA of the Th2 master transcription factor GATA3 is preferentially expressed in neonatal CD4(+) T cells. The Th2 phenotype of the IL-4(+)CD4(+) T cells could be reinforced in the presence of TGF-β. Although the IL-4(+)CD4(+) T cells most likely originate from CD31(+)CD4(+) T recent thymic emigrants, CD31 was downregulated prior to secretion of IL-4. Notably, the secretion of IL-4 requires a so far unidentified trigger in neonatal T cells. This emphasizes that cytokine expression and secretion are differentially regulated processes. Our data support the hypothesis of an endogenously poised cytokine profile in neonates and suggest a link between cytokine production and the developmental stage of an organism. The determination of the IL-4 isoform-expressing cells in humans might allow the identification of Th2 precursor cells, which could provide novel intervention strategies directed against Th2-driven immunopathologies such as allergies.

Topics: Female; GATA3 Transcription Factor; Gene Expression Regulation; Glycosylation; Humans; Hypersensitivity; Infant; Infant, Newborn; Interleukin-4; Male; Protein Isoforms; Th2 Cells; Transforming Growth Factor beta

Prevention of new IgE sensitizations has been described during allergen-specific immunotherapy. However, prospective data using a preventive approach in very young children who would benefit most are missing. We initiated a prospective pilot study investigating the safety, immunomodulatory, and sensitization-preventive effect of sublingual immunotherapy (SLIT) in mono/oligoclonally sensitized, clinically asymptomatic children 2-5 yr of age.. In this double-blinded, randomized, placebo-controlled pilot study, 31 mono-/oligosensitized children to house-dust mite or grass pollen were included. SLIT with the respective source (n = 15) or placebo (n = 16) was applied. After dose-up-phase therapy was continued for 2 yr. Parents recorded clinical events, vaccinations, and drug intake in a diary. Skin prick testing and specific IgE and IgG measurements were recorded at baseline, 12 and 24 months. At the same time, allergen-specific proliferation and IL10- and TGFβ-dependent Treg function were measured.. Preventive application of SLIT in young children was safe (no relevant side effects in 21,170 single applications). After 12 and 24 months of treatment, the rate of allergen-specific sensitization (specific IgE and SPT reactivity) was comparable in the treatment and the placebo group. However, verum-treated patients displayed a significant up-regulation of allergen-specific IgG (p < 0.05). Furthermore, IL10-dependent inhibition (p < 0.05) was observed in vitro in the treatment group but not in the placebo group.. Preventive SLIT is safe in children 2-5 yr of age and induces regulatory mechanisms involving allergen-specific IgG and IL10. Based on this pilot study, large-scale trials will need to investigate the modulation of sensitization and clinically relevant allergy.

Topics: Administration, Sublingual; Allergens; Animals; Antigens, Dermatophagoides; Asymptomatic Diseases; Cell Proliferation; Cells, Cultured; Child, Preschool; Desensitization, Immunologic; Double-Blind Method; Female; Follow-Up Studies; Humans; Hypersensitivity; Immune Tolerance; Immunoglobulin E; Immunoglobulin G; Interleukin-10; Lymphocyte Activation; Male; Pilot Projects; Placebos; Poaceae; Pollen; Prospective Studies; Pyroglyphidae; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

This study explored the effects of maternal probiotic supplementation on immune markers in cord blood (CB) and breast milk.. CB plasma and breast milk samples were collected from a cohort of women who had received daily supplements of either 6 x 10(9) CFU/day Lactobacillus rhamnosus HN001 (n=34), 9 x 10(9) CFU/day Bifidobacterium lactis HN019 (n=35) or a placebo (n=36) beginning 2-5 weeks before delivery and continuing for 6 months in lactating women. CB plasma and breast milk (collected at 3-7 days, 3 months and 6 months postpartum) were assayed for cytokines (IL-13, IFN-gamma, IL-6, TNF-alpha, IL-10, TGF-beta1) and sCD14. Breast milk samples were also assayed for total IgA.. Neonates of mothers who received a probiotic had higher CB IFN-gamma levels (P=0.026), and a higher proportion had detectable blood IFN-gamma levels, compared with the placebo group (P=0.034), although levels were undetectable in many infants. While this pattern was evident for both probiotics, when examined separately only the L. rhamnosus HN001 group showed statistically significant higher IFN-gamma levels (P=0.030) compared with the placebo group. TGF-beta1 levels were higher in early breast milk (week 1) from the probiotic groups (P=0.028). This was evident for the B. lactis HN019 group (P=0.041) with a parallel trend in the L. rhamnosus HN001 group (P=0.075). Similar patterns were seen for breast milk IgA, which was more readily detected in breast milk from both the B. lactis HN019 (P=0.008) and the L. rhamnosus HN001 group (P=0.011). Neonatal plasma sCD14 levels were lower in the B. lactis HN019 group compared with the placebo group (P=0.041).. The findings suggest that supplementation with probiotics in pregnancy has the potential to influence fetal immune parameters as well as immunomodulatory factors in breast milk.

Topics: Bifidobacterium; Breast Feeding; Cohort Studies; Cytokines; Female; Fetal Blood; Humans; Hypersensitivity; Immunoglobulin A; Infant, Newborn; Interferon-gamma; Lacticaseibacillus rhamnosus; Lipopolysaccharide Receptors; Milk, Human; Pregnancy; Pregnancy Complications; Prenatal Nutritional Physiological Phenomena; Probiotics; Transforming Growth Factor beta

The immunologic response to immunotherapy with dog extract is not well characterized.. The purpose of this study was to examine the immunologic response to 3 doses of dog extract expressed as their Can f 1 content.. Cluster immunotherapy was administered to 28 patients with dog allergy who were randomly assigned to 1 of 4 treatment arms: placebo or acetone-precipitated extract containing 0.6 mug, 3.0 mug, or 15.0 mug Can f 1 per 0.5 mL maintenance dose. Studies included titrated skin prick tests, the late cutaneous response, titrated nasal challenge with dog extract, and serum allergen-specific IgE and IgG(4). Dog allergen-stimulated lymphocyte proliferation was performed with measurement of secreted cytokines by ELISA and of intracellular cytokines by flow cytometry.. There was a significant dose-dependent response in suppression of titrated skin prick tests and suppression of the late cutaneous response. There was a significant increase from baseline in dog-specific IgG(4) in both the high-dose and low-dose groups and a dose-dependent suppression of secreted TNF-alpha and increase in secreted TGF-beta. There was a dose-dependent trend in suppression of secreted IL-4 with a significant decrease from baseline in the high-dose group. There were no significant changes in symptom scores; lymphocyte proliferation; secreted IFN-gamma, IL-10, or IL-5; or intracellular cytokine production.. The dose-response in immunologic parameters after immunotherapy with dog extract is similar to that previously demonstrated with cat extract.. The greatest and most consistent response is seen with a dose containing 15 mug Can f 1.

Topics: Allergens; Antibody Specificity; Antigens, Plant; Cells, Cultured; Desensitization, Immunologic; Dose-Response Relationship, Immunologic; Drug Administration Schedule; Humans; Hypersensitivity; Immunoglobulin G; Interleukin-4; Leukocytes, Mononuclear; Skin Tests; Transforming Growth Factor beta; Treatment Outcome; Tumor Necrosis Factor-alpha

The prevalence of atopic diseases is increasing throughout the Western world, and means of primary prevention are needed to reverse this trend. The role of breast-feeding, the best source of infant nutrition, in protection against atopic disease remains elusive. In this double-blinded, placebo-controlled study of 62 mother-infant pairs, it is shown that administering probiotics to the pregnant and lactating mother increased the immunoprotective potential of breast milk, as assessed by the amount of anti-inflammatory transforming growth factor beta2 (TGF-beta2) in the milk (2885 pg/mL [95% CI, 1624-4146] in mothers receiving probiotics vs 1340 pg/mL [95% CI, 978-1702] in mothers receiving placebo; P =.018). The risk of developing atopic eczema during the first 2 years of life in infants whose mothers received probiotics was significantly reduced in comparison with that in infants whose mothers received placebo (15% and 47%, respectively; relative risk, 0.32 [95% CI, 0.12-0.85]; P =.0098). Maternal atopy was a clear risk factor for atopic eczema in the infant. The infants most likely to benefit from maternal probiotic supplementation were those with an elevated cord blood IgE concentration. Administering probiotics during pregnancy and breast-feeding thus offers a safe and effective mode of promoting the immunoprotective potential of breast-feeding and provides protection against atopic eczema during the first 2 years of life.

Topics: Breast Feeding; Double-Blind Method; Female; Follow-Up Studies; Humans; Hypersensitivity; Infant; Infant, Newborn; Milk, Human; Pregnancy; Probiotics; Protective Agents; Transforming Growth Factor beta

Topics: Antigens, CD; Asthma; Dendritic Cells; GPI-Linked Proteins; Humans; Hypersensitivity; Inflammation; Neoplasm Proteins; Transforming Growth Factor beta

Asthma is a chronic airway disease. Allergic reactions and T helper (h)2 immune response play a key role in asthma occurrence. Cell therapy can control inflammation and remodeling responses in allergic asthma, and cytokines can change this effect. Therefore, in this study, the effect of treated cell therapy with IL-2 to control allergic asthma was studied. Bone marrow cells were extracted and co-cultured with IL-2 and the cells were used via intra-tracheal administration in allergic asthma mice. Levels of IL-4, IL-5, IL-13, Leukotriene B4 and C4, and remodeling factors were measured. At least, a histopathology test of lung tissue was done. Type2 cytokines, leukotrienes, remodeling factors, mucus secretion, goblet cell hyperplasia, peri-bronchial and peri-vascular inflammation were significantly (p˂0.05) decreased by treating with bone marrow-derived mononuclear cells (BMDMCs) and IL-2-BMDMCs. Treatment with IL-2-BMDMCs could significantly decrease IL-13, transforming growth factor (TGF)-β, HP levels, and mucus secretion (p˂0.05) compared to BMDMCs treatment. In this study, BMDMCs and IL-2-BMDMCs therapy could decrease inflammation, allergic, and remodeling factors in allergic asthma. Cell therapy with BMDMCs had a strong and notable effect on the control of allergic asthma pathophysiology when co-cultured and used with IL-2.

Topics: Animals; Asthma; Bone Marrow; Bronchoalveolar Lavage Fluid; Cytokines; Disease Models, Animal; Hypersensitivity; Inflammation; Interleukin-13; Interleukin-2; Leukocytes, Mononuclear; Lung; Mice; Mice, Inbred BALB C; Ovalbumin; Transforming Growth Factor beta

Dual-specificity phosphatase 8 (DUSP8) is a MAPK phosphatase that dephosphorylates and inactivates the kinase JNK. DUSP8 is highly expressed in T cells; however, the in vivo role of DUSP8 in T cells remains unclear. Using T cell-specific Dusp8 conditional KO (T-Dusp8 cKO) mice, mass spectrometry analysis, ChIP-Seq, and immune analysis, we found that DUSP8 interacted with Pur-α, stimulated interleukin-9 (IL-9) gene expression, and promoted Th9 differentiation. Mechanistically, DUSP8 dephosphorylated the transcriptional repressor Pur-α upon TGF-β signaling, leading to the nuclear export of Pur-α and subsequent IL-9 transcriptional activation. Furthermore, Il-9 mRNA levels were induced in Pur-α-deficient T cells. In addition, T-Dusp8-cKO mice displayed reduction of IL-9 and Th9-mediated immune responses in the allergic asthma model. Reduction of Il-9 mRNA levels in T cells and allergic responses of T-Dusp8-cKO mice was reversed by Pur-α knockout. Remarkably, DUSP8 protein levels and the DUSP8-Pur-α interaction were indeed increased in the cytoplasm of T cells from people with asthma and patients with atopic dermatitis. Collectively, DUSP8 induces TGF-β-stimulated IL-9 transcription and Th9-induced allergic responses by inhibiting the nuclear translocation of the transcriptional repressor Pur-α. DUSP8 may be a T-cell biomarker and therapeutic target for asthma and atopic dermatitis.

Topics: Active Transport, Cell Nucleus; Animals; Asthma; Dermatitis, Atopic; Dual-Specificity Phosphatases; Humans; Hypersensitivity; Inflammation; Interleukin-9; Mice; RNA, Messenger; Transcription Factors; Transforming Growth Factor beta

Topics: Eosinophilia; Humans; Hypersensitivity; Inflammation; Transforming Growth Factor beta

Topics: Allergens; Child, Preschool; Humans; Hypersensitivity; Immunoglobulin A; Milk, Human; Transforming Growth Factor beta; Tumor Necrosis Factor Ligand Superfamily Member 13

Helminths possibly down-modulate immune responses to airborne allergens through the induction of a regulatory network. The identification of helminths bioactive molecules is highly desirable, given their immunomodulatory potential which could be used in immunotherapies for allergy and autoimmune diseases. To investigate the immunoregulatory potential of the adult Toxocara canis crude extract and ten protein fractions of its extract, human peripheral blood mononuclear cells (PBMC) from 10 allergic and 9 non-allergic individuals were cultivated, in vitro, in the presence or absence of these antigens, and their supernatants were evaluated for cytokine production (TGF-β, IL-10, IL-12, TNF-α, IL-6, IL-5, IL13, and IL-17). To determine the cell viability, the PBMC were cultivated for 24 h in the presence of the antigens and, following, they were subjected to a cytotoxicity assay. The viability of the PBMC was not affected by incubation with the T. canis antigens. As some fractions stimulated the production of immunoregulatory (TGF-β and/or IL-10), IL-12 and Th1 (TNF-α) cytokines, without stimulating Th2 cytokines (IL-5 and IL13) and IL-17, it was proposed that they would be potential candidates for further studies, especially involving the purification and characterization of specific proteins, which could be tested separately to evaluate their specific role as adjuvants in immunotherapy for inflammatory diseases.

Topics: Adult; Animals; Cytokines; Humans; Hypersensitivity; Interleukin-10; Interleukin-12; Interleukin-13; Interleukin-17; Interleukin-5; Leukocytes, Mononuclear; Th1 Cells; Th2 Cells; Toxocara canis; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Several subsets of CD8

Topics: Animals; CD8-Positive T-Lymphocytes; Forkhead Transcription Factors; Humans; Hypersensitivity; Immunoglobulin E; Mice; Receptors, Chemokine; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Topics: Agar; Animals; Cattle; Cytokines; Female; Food Microbiology; Humans; Hypersensitivity; Immunoglobulin E; Infant; Interleukin-4; Lacticaseibacillus rhamnosus; Lactobacillus plantarum; Mice; Mice, Inbred BALB C; Probiotics; Transforming Growth Factor beta

Topics: Administration, Oral; Animals; Anti-Allergic Agents; beta-N-Acetylhexosaminidases; Caco-2 Cells; Cell Line, Tumor; Female; Humans; Hypersensitivity; Immunoglobulin E; Lactobacillus plantarum; Mice; Mice, Inbred BALB C; Passive Cutaneous Anaphylaxis; Transforming Growth Factor beta

Asthma is a heterogeneous disease characterized by multiples respiratory symptoms; this is a polygenic entity that involves a complex interaction of environmental factors and inherent to the individual. To understand the development of asthma, some phenotypes have been proposed.. This work's purpose was to explore different molecules related to asthma development and to define each phenotype's specific characteristics.. 96 adult patients diagnosed with asthma before any treatment were enrolled in the protocol. Spirometric parameters, circulating leukocytes, serum IgE, body mass index, exhaled nitric oxide (FENO), and leukotrienes (LTB4) in urine were determined in each patient. The presence of asthma phenotypes proposed by the Global Initiative for Asthma (GINA) were explored: A) Allergic asthma, B) Non-allergic asthma, C) Late-onset asthma, D) Asthma with persistent airflow limitation, and E) Asthma with overweight and obesity.. In the cohort analyzed, we found four of phenotypes proposed by GINA; however, these phenotypes overlapped, due to this, 4 groups were integrated with allergic, non-allergic and obese patients, which were the main phenotypes. The main overlap was that of patients not-obese allergic, and was characterized by earlier onset, elevated levels of IgE, LTB4 and inflammasome related cytokines. Non-allergic patients had a significant association between interleukin (IL)-18 and IL-18 binding protein (BP) with narrow ratio between these cytokines. Finally, LTB4 had remarkable capacity to discriminate between allergic and not allergic patients.. Asthmatic phenotypes exist as interrelated characteristics and not as discrete entities. High levels of leukotrienes and IgE are hallmarks in the allergic phenotype of asthma.

Topics: Adult; Age of Onset; Asthma; Biomarkers; Cytokines; Eosinophils; Female; Humans; Hypersensitivity; Immunoglobulin E; Inflammasomes; Inflammation Mediators; Intercellular Signaling Peptides and Proteins; Interleukin-18; Interleukin-8; Leukotrienes; Male; Middle Aged; Overweight; Phenotype; Transforming Growth Factor beta

Allergen-specific-immunotherapy (ASIT) can cause long-term resolution of allergic diseases, reduces drug use and chances of new allergen sensitization. Nevertheless, therapeutic vaccine and data on ASIT efficacy for cockroach (CR) allergy are relatively scarce. In this study, efficacy and mechanism of a novel intranasal vaccine consisting of liposome (L)-entrapped mixture of American CR (

Topics: Administration, Intranasal; Allergens; Animals; Arginine Kinase; Brugia malayi; Dendritic Cells; Desensitization, Immunologic; Disease Models, Animal; Hypersensitivity; Immunoglobulin E; Immunoglobulin G; Immunosuppressive Agents; Insect Proteins; Liposomes; Male; Mice; Mice, Inbred BALB C; Periplaneta; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Treatment Outcome; Vaccines

Airway remodeling happens in childhood asthma, in parallel with, but not necessarily subsequent to, airway inflammation. The differentiation of airway epithelial cells into myofibroblasts via epithelial-mesenchymal-transition (EMT) is one of the mechanisms underlying airway remodeling. This study aimed at identifying novel molecules involved in pediatric asthma-associated airway remodeling. Asthma model was established by challenging C57BL/6 mouse pups with ovalbumin (OVA). We found that the expression of Cadherin 11 (CDH11), a type II cadherin, was increased by OVA treatments in the airway epithelium. Our earlier microarray data suggested miRNA-451a-5p (miRNA-451a) as a potential regulator of CDH11. In contrast to CDH11, miRNA-451a expression decreased in the asthmatic lung. MiRNA-451a was then packaged into a lentivirus vector and systematically given to the asthmatic pups. Our data indicated that OVA-induced infiltration of inflammatory cells, including eosnophils, neutrophils, macrophages and lymphocytes, was reduced by miRNA-451a over-expression. EMT was initiated in asthmatic mice as demonstrated by increased alpha-smooth muscle actin (α-SMA) positive cells present in airway epithelium, which was inhibited by miRNA-451a. CDH11 elevation in vivo was also inhibited by miRNA-451a. Dual-Luciferase analysis further showed CDH11 as a novel valid target of miRNA-451a. Additionally, in vitro, EMT was triggered in human 16HBE airway epithelial cells by pro-fibrotic transforming growth factor β (TGF-β). Corresponding to the anti-EMT effects observed in vivo, miRNA-451a also inhibited TGF-β-induced collagen deposition in cultured airway epithelial cells by targeting in CDH11. In summary, our study demonstrates that the deregulated miRNA-451a-CDH11 axis contributes to airway remodeling in childhood asthma.

Topics: Airway Remodeling; Allergens; Animals; Animals, Newborn; Asthma; Cadherins; Cells, Cultured; Disease Models, Animal; Humans; Hypersensitivity; Male; Mice; Mice, Inbred C57BL; MicroRNAs; Ovalbumin; Respiratory Mucosa; Signal Transduction; Transforming Growth Factor beta

Allergic asthma (AA) is characterized as a Th2-biased airway inflammation that can develop lung inflammation and remodeling of the respiratory tract.

Topics: Animals; Asthma; Cells, Cultured; Disease Models, Animal; Disease Resistance; Goblet Cells; Humans; Hyperplasia; Hypersensitivity; Interleukin-6; Mice; Mice, Knockout; Pneumonia; Pneumonia, Pneumococcal; Respiratory Mucosa; RNA, Small Interfering; Signal Transduction; Streptococcus pneumoniae; Tight Junctions; Transforming Growth Factor beta

Although many immune cells can secrete TGF-β, whether all sources of TGF-β are functionally equivalent is unknown. In this issue, Turner et al. uncover the importance of T regulatory (Treg) cell-intrinsic Tgfb1 gene dose in the prevention of autoimmunity and allergic disease.

Topics: Autoimmunity; Humans; Hypersensitivity; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Transforming Growth Factor beta1

Allergic and autoimmune diseases comprise a group of inflammatory disorders caused by aberrant immune responses in which CD25+ Forkhead box P3-positive (FOXP3+) T regulatory (Treg) cells that normally suppress inflammatory events are often poorly functioning. This has stimulated an intensive investigative effort to find ways of increasing Tregs as a method of therapy for these conditions. One such line of investigation includes the study of how ligation of Toll-like receptors (TLRs) by CpG oligonucleotides (ODN) results in an immunostimulatory cascade that leads to induction of T-helper (Th) type 1 and Treg-type immune responses.. The present study investigated the mechanisms by which calf thymus mammalian double-stranded DNA (CT-DNA) and a synthetic methylated DNA CpG ODN sequence suppress in vitro lymphoproliferative responses to antigens, mitogens, and alloantigens when measured by [3H]-thymidine incorporation and promote FoxP3 expression in human CD4+ T cells in the presence of transforming growth factor (TGF) beta and interleukin-2 (IL-2).. Lymphoproliferative responses of peripheral blood mononuclear cells from four healthy subjects or nine subjects with systemic lupus erythematosus to CT-DNA or phytohemagglutinin (PHA) was measured by tritiated thymidine ([3H]-TdR) incorporation expressed as a stimulation index. Mechanisms of immunosuppressive effects of CT-DNA were evaluated by measurement of the degree of inhibition to lymphoproliferative responses to streptokinase-streptodornase, phytohemagglutinin (PHA), concanavalin A (Con A), pokeweed mitogen (PWM), or alloantigens by a Con A suppressor assay. The effects of CpG methylation on induction of FoxP3 expression in human T cells were measured by comparing inhibitory responses of synthetic methylated and nonmethylated 8-mer CpG ODN sequences by using cell sorting, in vitro stimulation, and suppressor assay.. Here, we showed that CT-DNA and a synthetic methylated DNA 8-mer sequence could suppress antigen-, mitogen-, and alloantigen-induced lymphoproliferation in vitro when measured by [3H]-thymidine. The synthetic methylated DNA CpG ODN but not an unmethylated CpG ODN sequence was shown to promote FoxP3 expression in human CD4+ T cells in the presence of TGF beta and IL-2. The induction of FoxP3+ suppressor cells is dose dependent and offers a potential clinical therapeutic application in allergic and autoimmune and inflammatory diseases.. The use of this methylated CpG ODN offers a broad clinical application as a novel therapeutic method for Treg induction and, because of its low cost and small size, should facilitate delivery via nasal, respiratory, gastrointestinal routes, and/or by injection, routes of administration important for vaccine delivery to target sites responsible for respiratory, gastrointestinal, and systemic forms of allergic and autoimmune disease.

Topics: Animals; Cattle; CD4-Positive T-Lymphocytes; Cell Proliferation; Cells, Cultured; CpG Islands; DNA; DNA Methylation; Forkhead Transcription Factors; Humans; Hypersensitivity; Immunosuppression Therapy; Immunotherapy; Isoantigens; Lupus Erythematosus, Systemic; Lymphocyte Activation; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Animals with impaired transforming growth factor (TGF)-β1 signaling developed spontaneous lethal autoimmune inflammationand autoimmune diseases. Moreover, evidence for modified TGF-β signaling in atopic dermatitis (AD) exists. Therefore, the goal of this study was to determine whether SB-431542, a potent and selective inhibitor of the TGF-β type 1 receptor (TGF-βR1), could attenuate such a severe reaction in mice. In addition, the molecular underpinnings the possible protective effects were also investigated. Repeated epicutaneous application of DNCB was performed on the ear and shaved dorsal skin of miceto induce AD-like symptoms and skin lesions. SB-431542 (1 mg/kg) was given by intra-peritoneal injection three times weekly for 3 weeks to assess the anti-pruritic effects. Serum levels of TGF-β1, TGF-βR1, latency-associated peptide (LAP), tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 were assessed by ELISA. Moreover, the gene expression of TNF-α, IL-1β and IL-6 were determined. Apoptotic pathway was evaluated by measuring the activity of caspase-3 and by staining skin sections with anti-caspase-3 antibodies. We found that SB-431542 alleviated DNCB-induced AD-like symptoms as quantified by skin lesion,dermatitisscore, ear thickness and scratching behavior. In parallel, SB-431542 blocked DNCB-induced elevation in serum levels of TNF-α, TGF-β1, TGF-βR1, LAP, IL-1β, IL-6 and IgE. The collective results indicate that SB-431542 partially suppresses DNCB-induced AD in micevia reduction of TGF-β1 signaling pathway associated with inhibition of inflammation and apoptosis.

Topics: Animals; Antioxidants; Benzamides; Biomarkers; Caspase 3; Dermatitis, Atopic; Dinitrochlorobenzene; Dioxoles; Disease Models, Animal; Enzyme Activation; Fibrosis; Gene Expression Regulation; Hypersensitivity; Inflammation; Inflammation Mediators; Mice, Inbred BALB C; Receptor, Transforming Growth Factor-beta Type I; Skin; Transforming Growth Factor beta

Colostrum is produced in the first days postpartum. It is a known source of immune mediators for a newborn within the first week of life. Although it is still unclear if colostrum composition varies between populations, recent data suggest differences. Hepatocyte growth factor (HGF); transforming growth factor-β (TGF-β) 1, 2, and 3; and immunoglobulin A (IgA) are key immunological components of colostrum that stimulate neonatal gastrointestinal and immune system development. We aimed to investigate the differences in the concentration between immune markers in the colostrum of mothers living in Burundi and Italy, and to identify the factors associated with differences. In this cross-sectional birth cohort study, a total of 99 colostrum samples from Burundian (

Topics: Adult; Breast; Breast Feeding; Burundi; Cohort Studies; Colostrum; Cross-Sectional Studies; Developed Countries; Developing Countries; Female; Hepatocyte Growth Factor; Humans; Hypersensitivity; Immunoglobulin A; Immunologic Factors; Infant, Newborn; Italy; Lactation; Milk, Human; Postpartum Period; Pregnancy; Transforming Growth Factor beta; Transforming Growth Factor beta2; Young Adult

The generation of the tolerogenic dendritic cells (DC) is not fully understood yet. Forkhead box protein-3 (Foxp3) is an important molecule in the immune tolerance. This study tests a hypothesis that DCs express Foxp3, which can be upregulated by Staphylococcal enterotoxin B (SEB).. The expression of Foxp3 by DCs was evaluated by real-time RT-PCR, Western blotting, flow cytometry, and chromatin immunoprecipitation assay.. Dendritic cells have the capacity to express Foxp3, which can be upregulated by exposure to SEB.

Topics: Animals; Dendritic Cells; Enterotoxins; Forkhead Transcription Factors; Hypersensitivity; Immune Tolerance; Immunotherapy; Interleukin-4; Mice; STAT6 Transcription Factor; Transforming Growth Factor beta; Up-Regulation

We investigated the effects of pan-class I PI3K inhibitor, ZSTK474 on vascular remodeling using a murine model of allergic vasculitis with eosinophil infiltration.. C57BL/6 mice were sensitized with OVA. The positive controls were exposed to aerosolized OVA daily for 7 days. The other group of mice were administered ZSTK474 (30 mg/kg, p.o. daily) in parallel with daily exposure to aerosolized OVA for 7 days. On the 3rd and 7th day, bronchoalveolar lavage (BAL) was performed and the lungs were excised for pathological analysis. Cell differentials were determined and the concentrations of IL-4, IL-5, IL-13 and TGF-βin BAL fluid were measured.. The total cell numbers and eosinophil numbers in BALF were greatly reduced in the ZSTK474-treated group on the 3rd and 7th day after exposure to OVA. The numbers of total white blood cells and eosinophils in the peripheral blood were significantly reduced in the ZSTK474-treated group on the 3rd and 7th day after exposure to OVA. The concentrations of IL-4, IL-5, and IL-13 in BAL fluids were also reduced significantly on the 3rd day in the ZSTK474-treated group. The concentrations of TGF-β in BAL fluids were also reduced significantly on the 3rd and 7th day in the ZSTK474-treated group. The pathological scores reduced significantly in the ZSTK474-treated group compared to the control group.. The PI3K inhibitor, ZSTK474 suppressed pulmonary vascular remodeling in the murine model of allergic vasculitis with eosinophil infiltration. PI3K signal transduction may have a critical role in the immunological process that induces allergic vasculitis.

Topics: Animals; Asthma; Disease Models, Animal; Eosinophils; Female; Hypersensitivity; Inflammation; Interleukin-13; Interleukin-4; Interleukin-5; Leukocyte Count; Lung; Mice; Mice, Inbred C57BL; Ovalbumin; Phosphoinositide-3 Kinase Inhibitors; Transforming Growth Factor beta; Triazines; Vascular Remodeling; Vasculitis

Topics: Airway Remodeling; Asthma; Cell Adhesion Molecules; Dexamethasone; Eosinophils; Epithelial Cells; Fibroblasts; Humans; Hypersensitivity; Inflammation; Interleukin-5; Macrophage-1 Antigen; Th2 Cells; Transforming Growth Factor beta; Up-Regulation; Vascular Cell Adhesion Molecule-1

The prevalence of allergic diseases is globally increasing. We have previously described that glycomacropeptide (GMP), a bioactive milk peptide, has therapeutic value in experimental models of skin hypersensitivity, anaphylaxis, and asthma, as it prevents an excessive T helper type 2 cell immune response. The aim of this study was to analyze the effect of GMP on key elements directly involved in the development or control of allergy, in order to improve the precise knowledge about its mechanism of action.. Rats were systemically sensitized with ovalbumin and orally treated with GMP. Levels of Lactobacillus, Bifidobacterium, and Bacteroides were analyzed in their feces. Splenocytes were isolated and the production of transforming growth factor (TGF)-β by allergens was measured. Intradermal skin reactions were developed to evaluate in vivo activation of mast cells. Peritoneal mast cells were isolated and activated by the allergen, and histamine secretion was determined.. GMP administration increased the amount of intestinal Lactobacillus and Bifidobacterium of allergen-sensitized animals after 3 days of treatment. The increase in Bacteroides was also significant, but only after 17 days of GMP administration. Ten days after treatment cessation, Lactobacillus and Bacteroides were still elevated. GMP intake also elevated the production of TGF-β in the splenocytes of sensitized animals. In addition, treatment with GMP attenuated mast cell activation by the allergen and inhibited histamine secretion, without affecting the number of mast cells.. The prebiotic action of GMP on allergy-protective microbiota, an increase in TGF-β production, and a reduction in mast cell response to allergens are novel mechanisms that explain the antiallergic activity of GMP.

Topics: Animals; Caseins; Disease Models, Animal; Feces; Gastrointestinal Microbiome; Histamine Release; Hypersensitivity; Immunization; Mast Cells; Peptide Fragments; Rats; Skin; Transforming Growth Factor beta

We sought to modulate mucosal immune responses using neonatal vaccination to avert the development of allergic airways disease (AAD). Pulmonary pathology in AAD is driven by T helper (TH)2 cytokines, in particular interleukin (IL)4 and IL13, the expression and actions of which are regulated by the transcription factor STAT6. We developed a peptide homolog of STAT6, STAT6-IP. Neonatal mice given, intranasally, STAT6-IP, in an effort to modulate de novo airways immune responses, developed tolerance following subsequent allergen sensitization, with either ovalbumin or ragweed allergens, as demonstrated by reduced TH2 cytokines and specific immunoglobulin (Ig)E and the significant increases in the latency-associated peptide (LAP)(+) T-regulatory (Treg) cell subset and expression of transforming growth factor (TGF)-β. This regulatory phenotype was transferrable by CD4(+) T cells or CD11c(+) dendritic cells (DCs) derived from STAT6-IP-vaccinated mice. Anti-TGF-β treatment during allergen sensitization, however, re-established the pro-inflammatory TH2 response. Thus, neonatal STAT6-IP vaccination induces prospective TGF-β-dependent tolerance to allergen and constitutes a novel highly effective immunomodulatory allergy prevention strategy.

Topics: Adoptive Transfer; Allergens; Animals; Animals, Newborn; Asthma; Cell Separation; Desensitization, Immunologic; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Hypersensitivity; Immune Tolerance; Mice; Mice, Inbred BALB C; Real-Time Polymerase Chain Reaction; STAT6 Transcription Factor; Transforming Growth Factor beta; Vaccines, Subunit

Exposure to cockroach allergen leads to allergic sensitization and increased risk of developing asthma. Aryl hydrocarbon receptor (AhR), a receptor for many common environmental contaminants, can sense not only environmental pollutants but also microbial insults. Mesenchymal stem cells (MSCs) are multipotent progenitor cells with the capacity to modulate immune responses. In this study, we investigated whether AhR can sense cockroach allergens and modulate allergen-induced lung inflammation through MSCs. We found that cockroach allergen-treated AhR-deficient (AhR(-/-)) mice showed exacerbation of lung inflammation when compared with wild-type (WT) mice. In contrast, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an AhR agonist, significantly suppressed allergen-induced mouse lung inflammation. MSCs were significantly reduced in cockroach allergen-challenged AhR(-/-) mice as compared with WT mice, but increased in cockroach allergen-challenged WT mice when treated with TCDD. Moreover, MSCs express AhR, and AhR signaling can be activated by cockroach allergen with increased expression of its downstream genes cyp1a1 and cyp1b1. Furthermore, we tracked the migration of i.v.-injected GFP(+) MSCs and found that cockroach allergen-challenged AhR(-/-) mice displayed less migration of MSCs to the lungs compared with WT. The AhR-mediated MSC migration was further verified by an in vitro Transwell migration assay. Epithelial conditioned medium prepared from cockroach extract-challenged epithelial cells significantly induced MSC migration, which was further enhanced by TCDD. The administration of MSCs significantly attenuated cockroach allergen-induced inflammation, which was abolished by TGF-β1-neutralizing Ab. These results suggest that AhR plays an important role in protecting lungs from allergen-induced inflammation by modulating MSC recruitment and their immune-suppressive activity.

Topics: Allergens; Animals; Antibodies, Blocking; Asthma; Cell Movement; Cells, Cultured; Cockroaches; Culture Media, Conditioned; Cytochrome P-450 CYP1A1; Cytochrome P-450 CYP1B1; Epithelial Cells; Hypersensitivity; Immunization; Insect Proteins; Mesenchymal Stem Cells; Mice; Mice, Knockout; Pneumonia; Polychlorinated Dibenzodioxins; Receptors, Aryl Hydrocarbon; Transforming Growth Factor beta

Asthma is a chronic airway disorder characterized by recurrent attacks of breathlessness and wheezing, affecting 300 million people around the world (available at: www.who.int). To date, genetic factors associated with asthma susceptibility have been unable to explain the full etiology of asthma. Recent studies have demonstrated that the epigenetic disruption of gene expression plays an equally important role in the development of asthma through interaction with our environment. We sensitized 6-week-old C57BL/6J mice with house-dust-mite (HDM) extracts intraperitoneally followed by 5 weeks of exposure to HDM challenges (three times a week) intratracheally. HDM-exposed mice showed an increase in airway hyper-responsiveness (AHR) and inflammation together with structural remodeling of the airways. We applied methylated DNA immunoprecipitation-next generation sequencing (MeDIP-seq) for profiling of DNA methylation changes in the lungs in response to HDM. We observed about 20 million reads by a single-run of massive parallel sequencing. We performed bioinformatics and pathway analysis on the raw sequencing data to identify differentially methylated candidate genes in HDM-exposed mice. Specifically, we have revealed that the transforming growth factor beta signaling pathway is epigenetically modulated by chronic exposure to HDM. Here, we demonstrated that a specific allergen may play a role in AHR through an epigenetic mechanism by disrupting the expression of genes in lungs that might be involved in airway inflammation and remodeling. Our findings provide new insights into the potential mechanisms by which environmental allergens induce allergic asthma and such insights may assist in the development of novel preventive and therapeutic options for this debilitative disease.

Topics: Animals; Asthma; Bronchoalveolar Lavage Fluid; Cells, Cultured; Computational Biology; DNA Methylation; Epigenesis, Genetic; Gene Expression Profiling; High-Throughput Nucleotide Sequencing; Hypersensitivity; Immunoprecipitation; Inflammation; Lung; Male; Mice; Mice, Inbred C57BL; Pyroglyphidae; Signal Transduction; Trachea; Transforming Growth Factor beta

Allergic asthma is characterized by chronic airway remodeling, which is associated with the expression of extracellular matrix proteins (ECM) by TGF-β. However, to date there are no reports demonstrating that structural proteins are directly expressed in mast cells. This study aimed to investigate whether ECM proteins are expressed in mast cells activated with antigen/antibody reaction, and whether the resolution effects of irradiation or 8-oxo-dG may contribute to allergic asthma prevention. Bone marrow-derived mast cells (BMMCs) were activated with DNP-HSA/anti-DNP IgE antibody (act-BMMCs). C57BL/6 mice were sensitized and challenged with ovalbumin (OVA) to induce allergic asthma. Mice were treated orally with 8-oxo-dG or exposed to whole body irradiation (using (137)Cs gamma ray at a dose of 0.5 Gy) for three consecutive days 24 h after OVA challenge. Expression of extracellular matrix (ECM) proteins, TGF-β signaling molecules and NF-κB/AP-1 was determined in the BMMCs, bronchoalveolar lavage (BAL) cells or lung tissues using Western blot, polymerase chain reaction (PCR) and electrophoretic mobility shift assay (EMSA), respectively. Act-BMMCs increased expression of ECM proteins, TGF-β/TGF-β receptor I, TGF-β signaling molecules and cytokines; and increased both NF-κB and AP-1 activity. In addition, the population of mast cells; expression of mast cell markers, TGF-β signaling molecules, ECM proteins/amounts; OVA-specific serum IgE level; numbers of goblet cells; airway hyperresponsiveness; cytokines/chemokines were increased in BAL cells and lung tissues of OVA-challenged mice. All of the above end points were reduced by irradiation or 8-oxo-dG in vitro and in vivo, respectively. The data suggest that mast cells induce expression of ECM proteins through TGF-β produced in inflammatory cells of OVA mice and that post treatment of irradiation or 8-oxo-dG after OVA-challenge may reduce airway remodeling through down-regulating mast cell re-activation by TGF-β/Smad signals.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Airway Remodeling; Animals; Bone Marrow Cells; Bronchoalveolar Lavage Fluid; Deoxyguanosine; Dose-Response Relationship, Radiation; Electrophoretic Mobility Shift Assay; Extracellular Matrix Proteins; Female; Hypersensitivity; Mast Cells; Mice; Mice, Inbred C57BL; Ovalbumin; Signal Transduction; Transforming Growth Factor beta

Rapamycin has been reported to inhibit mesenchymal cell proliferation in a murine model of pulmonary fibrosis. In the present study, we examined the effects of rapamycin on vascular remodeling including intraluminal myofibroblast proliferation in a murine model of allergic vasculitis with eosinophil infiltration.. C57BL/6 mice were sensitized with ovalbumin (OVA) and alum. The positive controls were exposed to aerosolized OVA daily for 7 days. The other group of mice was administered with rapamycin (1mg/kg) intraperitoneally, in parallel with daily exposure to aerosolized OVA for 7 days. On the 3rd and 7th day, bronchoalveolar lavage (BAL) was performed and the lungs were excised for pathological analysis. Cell differentials were determined and concentrations of IL-4, IL-5, IL-13 and TGF-β in the BAL fluid (BALF) were measured. Semi-quantitative analysis of pathological changes in the pulmonary arteries was evaluated according to the severity of vasculitis.. The number of eosinophils in BALF was reduced significantly in the mice treated with rapamycin compared to the positive control. There was a significant decrease in the TGF-β concentration of the BALF in the rapamycin-treated group compared to that of the positive control. The pathological scores were reduced significantly in the rapamycin-treated group compared to the positive control group. Intraluminal myofibroblasts in pulmonary arteries were reduced dramatically in the rapamycin-treated group compared to the positive control group.. Rapamycin suppressed pulmonary vascular remodeling in a murine model of allergic vasculitis with eosinophil infiltration through reducing eosinophil infiltration and TGF-β production in the lung and inhibition against biological action of TGF-β.

Topics: Animals; Cell Proliferation; Disease Models, Animal; Disease Progression; Eosinophils; Female; Humans; Hypersensitivity; Immunosuppressive Agents; Lung Diseases; Mice; Mice, Inbred C57BL; Myofibroblasts; Pulmonary Artery; Sirolimus; Transforming Growth Factor beta; Vascular Remodeling; Vasculitis

Topics: Allergens; Epitopes, T-Lymphocyte; Humans; Hypersensitivity; Immune Tolerance; Immunotherapy; Interleukin-10; Switzerland; Transforming Growth Factor beta

Our and others' previous studies have shown that Schistosoma japonicum (SJ) infection can inhibit allergic reactions. We recently reported that DCs played an important role in SJ infection-mediated inhibition of allergy, which was associated with enhanced IL-10 and T regulatory cell responses. Here, we further compared the role of CD8α(+) DC and CD8α(-) DC subsets for the inhibitory effect. We sorted CD8α(+) DC (SJCD8α(+) DC) and CD8α(-) DC (SJCD8α(-) DC) from SJ-infected mice and tested their ability to modulate allergic responses in vivo. The data showed that the adoptive transfer of SJCD8α(-) DC was much more efficient than SJCD8α(+) DC for the suppression of allergic airway eosinophilia, mucus overproduction, antigen-specific IgE responses, and Th2 cytokines (IL-4 and IL-5). More importantly, we found that the transfer of SJCD8α(-) DC, but not SJCD8α(+) DC, significantly increased IL-10 and TGF-β production following OVA exposure. As control, the transfer of DC subsets from naïve mice had no significant effect on allergic inflammation. In addition, SJCD8α-DC expressed significantly higher IL-10 but lower IL-12, CD80 and CD86 than SJCD8α(+) DC, fitting a tolerogenic phenotype. The results suggest that CD8α(-) DC is the predominant DC subset which is involved in the parasitic infection-mediated inhibition of allergic inflammation and possibly through enhancing immunomodulatory cytokine (IL-10 and TGF-β) production.

Topics: Adoptive Transfer; Animals; Antigens, Helminth; CD11b Antigen; Dendritic Cells; Female; Hypersensitivity; Interleukin-10; Mice; Mice, Inbred BALB C; Ovalbumin; Pneumonia; Schistosomiasis japonica; T-Lymphocytes, Helper-Inducer; Transforming Growth Factor beta

One third of the human population is currently infected by one or more species of parasitic helminths. Certain helminths establish long-term chronic infections resulting in a modulation of the host's immune system with attenuated responsiveness to "bystander" antigens such as allergens or vaccines. In this study we investigated whether parasite-derived products suppress the development of allergic inflammation in a mouse model. We show that extract derived from adult male Oesophagostomum dentatum (eMOD) induced Th2 and regulatory responses in BALB/c mice. Stimulation of bone marrow-derived dendritic cells induced production of regulatory cytokines IL-10 and TGF-beta. In a mouse model of birch pollen allergy, co-administration of eMOD with sensitizing allergen Bet v 1 markedly reduced the production of allergen-specific antibodies in serum as well as IgE-dependent basophil degranulation. Furthermore, eMOD prevented the development of airway inflammation, as demonstrated by attenuation of bronchoalveolar lavages eosinophil influx, peribronchial inflammatory infiltrate, and mucus secretion in lungs and IL-4 and IL-5 levels in lung cell cultures. Reduced secretion of Th2-related cytokines by birch pollen-re-stimulated splenocytes and mesenteric lymph node cells was observed in eMOD-treated/sensitized and challenged mice in comparison to sensitized and challenged controls. The suppressive effects of eMOD were heat-stable. Immunization with model antigens in the presence of eMOD reduced production of antibodies to thymus-dependent but not to thymus-independent antigen, suggesting that suppression of the immune responses by eMOD was mediated by interference with antigen presenting cell or T helper cell function but did not directly suppress B cell function. In conclusion, we have shown that eMOD possesses immunomodulatory properties and that heat-stable factors in eMOD are responsible for the dramatic suppression of allergic responses in a mouse model of type I allergy. The identification and characterization of parasite-derived immune-modulating molecules might have potential for designing novel prophylactic/therapeutic strategies for immune-mediated diseases.

Topics: Allergens; Animals; Antigens, Plant; Basophils; Bystander Effect; Complex Mixtures; Dendritic Cells; Humans; Hypersensitivity; Immunity, Innate; Immunoglobulin E; Immunomodulation; Interleukin-10; Male; Mice; Mice, Inbred BALB C; Oesophagostomum; Pollen; T-Lymphocytes, Regulatory; Th2 Cells; Thymus Gland; Transforming Growth Factor beta

Insect bite hypersensitivity (IBH) is a recurrent allergic dermatitis of horses with similarities to human atopic eczema, caused by bites of insects of the genus Culicoides. Previous studies suggested a dysregulated T cell tolerance to Culicoides allergen in IBH-affected horses.. We have investigated whether the suppressive function of CD4(+) CD25(high) cells is impaired in IBH-affected horses and possible ways to restore it.. CD4(+) CD25(-) cells sorted from peripheral blood mononuclear cells (PBMC) were stimulated with irradiated autologous PBMC pulsed with Culicoides or tetanus toxoid as control antigen, in the presence of CD4(+) CD25(high) cells. Furthermore, Culicoides-specific CD4(+) CD25(high) regulatory cells were expanded or induced from CD4(+) CD25(-) cells in vitro in the presence of a combination of rIL-2 and rTGF-β1 (rIL-2/rTGF-β1) or of retinoic acid and rapamycin (RetA/Rapa). Proliferation was determined by [(3) H] thymidine incorporation and cytokine production measured by flow cytometry.. The ability of Culicoides- but not tetanus-stimulated CD4(+) CD25(high) cells to suppress proliferation of CD4(+) CD25(-) cells was significantly lower in IBH-affected horses (28%) than in healthy controls (86%). The decreased suppression in IBH-affected horses was associated with a significantly higher proportion of IL-4(+) cells and a lower percentage of FoxP3(+) IL-10(+) compared to controls. Addition of rIL-2/rTGF-β1 or of RetA/Rapa to Culicoides-stimulated CD4(+) CD25(high) cells from IBH-affected horses significantly increased the proportion of FoxP3(+) IL-10(+) cells. We also found that RetA/Rapa induced a more significant decrease in the frequency of IL-4(+) cells than rIL-2/rTGF-β1. Moreover, the suppressive activity of Culicoides-stimulated CD4(+) CD25(high) cells was significantly restored by both rIL-2/rTGF-β1and RetA/Rapa, albeit in an antigen-unspecific manner. In contrast, in vitro induced Culicoides-specific CD4(+) CD25(high) cells suppressed proliferation of CD4(+) CD25(-) cells in an antigen-specific manner.. The in vitro induction of functional allergen-specific Treg cells in IBH-affected horses suggests a potential therapeutic use of these cells in allergy.

Topics: Allergens; Animals; CD4 Antigens; Cytokines; Epitopes, T-Lymphocyte; Female; Forkhead Transcription Factors; Horses; Hypersensitivity; Immune Tolerance; Insect Bites and Stings; Interleukin-2; Interleukin-2 Receptor alpha Subunit; Lymphocyte Activation; Male; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

A reproducible method to inhibit allergic immune responses is accomplished with hi-dose Ag sensitization, via intraperitoneal (IP) injection. However, the role of CD4+ CD25+ FoxP3+ T regulatory cells (Treg) in this process is unknown, as is whether such modulation extends to ocular allergy. We therefore determined herein whether hi-dose sensitization modulates ocular allergy, and whether CD4+ CD25+ FoxP3+ Treg are involved. C57BL/6 mice were IP sensitized via low-dose (100 µg) versus hi-dose (1000 µg) ovalbumin (OVA), in aluminum hydroxide (1 mg) and pertussis-toxin (300 ng). Other mice received anti-CD25 Ab (PC61) to ablate Treg during sensitization. In another experiment, Treg from hi-dose sensitized mice were adoptively transferred into low-dose sensitized mice. Once daily OVA challenges were administered. Clinical signs, IgE, T cell cytokines, and eosinophils were assessed. Data revealed that hi-dose, but not low-dose, sensitization led to allergy modulation, indicated by decreased clinical signs, serum IgE levels, Th2 recall responses, and eosinophil recruitment. T cells from hi-dose sensitized mice showed a robust increase in TGF-b production, and Treg from these mice were able to efficiently suppress effector T cell proliferation in vitro. In addition, in vivo Treg ablation in hi-dose sensitized mice revoked allergy modulation. Lastly, Treg from hi-dose sensitized mice were able to adoptively transfer allergy modulation to their low-dose sensitized counterparts. Collectively, these findings indicate that modulation to hi-dose sensitization, which is extended to ocular allergy, occurs in a Treg-dependent manner. In addition, our data suggest that hi-dose sensitization may henceforth facilitate the further examination of CD4+ CD25+ FoxP3+ Treg in allergic disease.

Topics: Animals; Antigens; Cell Proliferation; Cytokines; Eosinophils; Forkhead Transcription Factors; Hypersensitivity; Immunization; Immunoglobulin E; Interleukin-2 Receptor alpha Subunit; Male; Mice; Mice, Inbred C57BL; Ovalbumin; T-Lymphocytes, Regulatory; Th2 Cells; Transforming Growth Factor beta

The pathophysiology of asthma involves allergic inflammation and remodelling in the airway and airway hyperresponsiveness (AHR) to cholinergic stimuli, but many details of the specific underlying cellular and molecular mechanisms remain unknown. Periostin is a matricellular protein with roles in tissue repair following injury in both the skin and heart. It has recently been shown to be up-regulated in the airway epithelium of asthmatics and to increase active TGF-β. Though one might expect periostin to play a deleterious role in asthma pathogenesis, to date its biological role in the airway is unknown.. To determine the effect of periostin deficiency on airway responses to inhaled allergen.. In vivo measures of airway responsiveness, inflammation, and remodelling were made in periostin deficient mice and wild-type controls following repeated intranasal challenge with Aspergillus fumigatus antigen. In vitro studies of the effects of epithelial cell-derived periostin on murine T cells were also performed.. Surprisingly, compared with wild-type controls, periostin deficient mice developed increased AHR and serum IgE levels following allergen challenge without differences in two outcomes of airway remodelling (mucus metaplasia and peribronchial fibrosis). These changes were associated with decreased expression of TGF-β1 and Foxp3 in the lungs of periostin deficient mice. Airway epithelial cell-derived periostin-induced conversion of CD4(+) CD25(-) cells into CD25(+) , Foxp3(+) T cells in vitro in a TGF-β dependent manner.. Allergen-induced increases in serum IgE and bronchial hyperresponsiveness are exaggerated in periostin deficient mice challenged with inhaled aeroallergen. The mechanism of periostin's effect as a brake on allergen-induced responses may involve augmentation of TGF-β-induced T regulatory cell differentiation.

Topics: Airway Remodeling; Animals; Antigens, Fungal; Aspergillus fumigatus; Asthma; Bronchial Hyperreactivity; Cell Adhesion Molecules; Disease Models, Animal; Hypersensitivity; Immunoglobulin E; Inflammation; Lung; Mice; Mice, Inbred C57BL; Transforming Growth Factor beta

In allergic diseases, immune responses are induced by normally well-tolerated allergens, which result in chronic inflammation characterized by antibody secretion and T cell activation. For almost 100 years, allergen-specific immunotherapy (allergen-SIT) has been the potentially curative and antigen-specific method for the treatment of allergic diseases. Allergen-SIT alters the course of allergic diseases and can reduce allergic symptoms and medication use. The key mechanism behind allergen-SIT is the induction of peripheral T cell tolerance by altering the balance between Th cells and regulatory T cells. Both naturally occurring thymus-derived FOXP3(+)CD4(+)CD25(+) regulatory T cells and inducible type 1 regulatory T cells suppress the development of allergic diseases via several mechanisms including suppression of dendritic cells, Th cells, mast cells, eosinophils and basophils; suppression of inflammatory cell migration to tissues; and decrease of the ratio between allergen-specific IgE and IgG4 antibodies. These effects are mainly mediated by the suppressive cytokines IL-10 and TGF-β. Knowledge of this molecular basis is crucial to understanding the regulation of the immune response and their possible therapeutic applications for allergic diseases.

Topics: Allergens; Desensitization, Immunologic; Humans; Hypersensitivity; Immune Tolerance; Immunoglobulin E; Immunoglobulin G; Immunosuppression Therapy; Interleukin-10; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Allergy is one of the most common diseases with constantly increasing incidence. The identification of prognostic markers pointing to increased risk of allergy development is of importance. Cord blood represents a suitable source of cells for searching for such prognostic markers. In our previous work, we described the increased reactivity of cord blood cells of newborns of allergic mothers in comparison to newborns of healthy mothers, which raised the question of whether or not this was due to the impaired function of regulatory T cells (T(regs)) in high-risk children. Therefore, the proportion and functional properties of T(regs) in cord blood of children of healthy and allergic mothers were estimated by flow cytometry. The proportion of T(regs) [CD4(+)CD25(high)CD127(low) forkhead box protein 3 (FoxP3(+))] in cord blood of children of allergic mothers tends to be higher while, in contrast, the median of fluorescence intensity of FoxP3 was increased significantly in the healthy group. Intracellular presence of regulatory cytokines interleukin (IL)-10 and transforming growth factor (TGF)-beta was also higher in T(regs) of children of healthy mothers. Although we detected an increased proportion of T(regs) in cord blood of children of allergic mothers, the functional indicators (intracellular presence of regulatory cytokines IL-10 and TGF-beta, median of fluorescence intensity of FoxP3) of those T(regs) were lower in comparison to the healthy group. We can conclude that impaired function of T(regs) in cord blood of children of allergic mothers could be compensated partially by their increased number. Insufficient function of T(regs) could facilitate allergen sensitization in high-risk individuals after subsequent allergen encounter.

Topics: Case-Control Studies; CD4 Antigens; Female; Fetal Blood; Flow Cytometry; Forkhead Transcription Factors; Humans; Hypersensitivity; Infant, Newborn; Interleukin-10; Interleukin-2 Receptor alpha Subunit; Interleukin-7 Receptor alpha Subunit; Pregnancy; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Allergic asthma is an inflammatory disorder characterized by infiltration of the airway wall with inflammatory cells driven mostly by activation of Th2-lymphocytes, eosinophils and mast cells. There is a link between increased allergy and a reduction of some infections in Western countries. Epidemiological data also show that respiratory allergy is less frequent in people exposed to orofecal and foodborne microbes such as Toxoplasma gondii. We previously showed that both acute and chronic parasite T. gondii infection substantially blocked development of airway inflammation in adult BALB/c mice. Based on the high levels of IFN-γ along with the reduction of Th2 phenotype, we hypothesized that the protective effect might be related to the strong Th1 immune response elicited against the parasite. However, other mechanisms could also be implicated. The possibility that regulatory T cells inhibit allergic diseases has received growing support from both animal and human studies. Here we investigated the cellular mechanisms involved in T. gondii induced protection against allergy. Our results show for the first time that thoracic lymph node cells from mice sensitized during chronic T. gondii infection have suppressor activity. Suppression was detected both in vitro, on allergen specific T cell proliferation and in vivo, on allergic lung inflammation after adoptive transference from infected/sensitized mice to previously sensitized animals. This ability was found to be contact-independent and correlated with high levels of TGF-β and CD4(+)FoxP3(+) cells.

Topics: Animals; Asthma; Bronchoalveolar Lavage; CD4 Antigens; Forkhead Transcription Factors; Hypersensitivity; Inflammation; Interferon-gamma; Lymph Nodes; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Knockout; Respiratory Hypersensitivity; Th2 Cells; Toxoplasma; Toxoplasmosis; Transforming Growth Factor beta

Mice lacking the C-type lectin receptor CD69 develop exacerbated forms of arthritis, contact dermatitis, allergic asthma, and autoimmune myocarditis. Because the immune responses in these diseases are largely mediated by a balance between proinflammatory subsets of T effector cells called T helper (T(H)) 17 cells and regulatory T cells, these findings indicate a previously unappreciated regulatory role for CD69 in modulating T lymphocyte differentiation toward the T(H)17 lineage and suggest a role in regulatory T cell function. CD69 promotes activation of the Jak3-signal transducer and activator of transcription 5 (Stat5) signaling pathway, which inhibits T(H)17 cell differentiation, thus providing a mechanistic link between CD69 and the regulation of T(H)17 responses. This evidence underscores the potential of CD69 as target in the treatment of autoimmune and allergic diseases and is consistent with mounting evidence linking CD69 to regulatory T cell subsets.

Topics: Animals; Antigens, CD; Antigens, Differentiation, T-Lymphocyte; Arthritis, Experimental; Autoimmune Diseases; Cell Differentiation; Humans; Hypersensitivity; Inflammation; Lectins, C-Type; Mice; Mice, Knockout; Signal Transduction; STAT5 Transcription Factor; T-Lymphocytes, Regulatory; Th17 Cells; Transforming Growth Factor beta

We evaluated allergy/hypersensitivity clinical markers and their correlation with Helicobactor pylori infection in children and adults to analyze how early acquisition of H. pylori could modulate allergic disorder expression.. H. pylori presence was assessed by the rapid urease test and histology of antrum biopsies in 165 patients. Skin tests, serum IgE, and two clinical allergy questionnaires were performed. Allergy severity was operationally defined using a combined score. Findings were correlated with H. pylori status and cytotoxin-associated gene A presence in pediatric and adult patients. Transforming growth factor β (TGF-β) levels were measured by an enzyme-linked immunosorbent assay in serum and gastric biopsies of H. pylori (+) patients.. H. pylori (-) children had more positive skin tests to a higher number of antigens than H. pylori (+) children (P<0.05). Operationally defined allergy inversely correlates with H. pylori infection in children, but not in adults. The percentage of H. pylori infection was lower in children with severe allergy (32.3%) compared with children with mild allergy (43.4%) or no allergy (64.3%) (P<0.05). Colonization with virulent strains (cytotoxin-associated gene A+) showed a nonsignificant inverse correlation with severity of allergies in pediatric patients. H. pylori-infected children, but not adults, without allergy markers showed increased levels of TGF-β compared with allergic children both in serum and gastric mucosa (P<0.05).. There was a strong inverse correlation between allergy markers and H. pylori infection in pediatric patients associated with elevated levels of TGF-β locally and systemically. H. pylori-associated chronic gastritis might downregulate clinical allergy expression.

Topics: Adolescent; Adult; Age Factors; Child; Cytokines; Female; Gastric Mucosa; Gastritis; Gastroscopy; Helicobacter Infections; Helicobacter pylori; Humans; Hypersensitivity; Immunoglobulin E; Male; Middle Aged; Pyloric Antrum; Skin Tests; Transforming Growth Factor beta; Young Adult

Regulation of tryptophan metabolism by indoleamine 2,3-dioxygenase (IDO) in dendritic cells (DCs) is a highly versatile modulator of immunity. In inflammation, interferon-γ is the main inducer of IDO for the prevention of hyperinflammatory responses, yet IDO is also responsible for self-tolerance effects in the longer term. Here we show that treatment of mouse plasmacytoid DCs (pDCs) with transforming growth factor-β (TGF-β) conferred regulatory effects on IDO that were mechanistically separable from its enzymic activity. We found that IDO was involved in intracellular signaling events responsible for the self-amplification and maintenance of a stably regulatory phenotype in pDCs. Thus, IDO has a tonic, nonenzymic function that contributes to TGF-β-driven tolerance in noninflammatory contexts.

Topics: Adaptive Immunity; Animals; Dendritic Cells; Humans; Hypersensitivity; Immune Tolerance; Indoleamine-Pyrrole 2,3,-Dioxygenase; Interferon-gamma; Mice; Mice, Inbred BALB C; Mice, Knockout; Signal Transduction; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Tryptophan

MyD88 is a major toll-like receptor (TLR) adaptor to activate NF-κB, which acts as a mater switch for allergic inflammation disease. Sterile hust dust extracts have been reported with TLR-dependent immunostimulatory activities. The aim of this study was to evaluate whether Dermatophagoides pteronyssinus (Der p) immunotherapy may increase IL-10+ CD4+ CD25+ T cells with modulating MyD88 signaling proteins, to decrease NF-κB expression. Peripheral blood mononuclear cells were isolated from patients before and after 1 yr of Der p immunotherapy, and also from matched control subjects. After 2 days of Der p-2 stimulation, intracellular IL-10 and Foxp3 expression of CD4(+) CD25(+) T cells were measured by flow-cytometry. The expression of IL-1 receptor-associated kinase (IRAK)-1 in cytoplasm and IFN-regulator factor-3 (IRF-3) with NF-κB/p65 in nuclei was determined by Western-blot analysis. Patients undergoing immunotherapy produced more soluble CD14, IL-10, and TGF-β that correlated with FEV(1) improvement (p < 0.05). In the immunotherapy group, the number of Foxp3+ CD4+ Treg cells increased more than the baseline status (25.06 ± 4.19 vs. 16.08 ± 3.54, p < 0.05). Additionally, increased IL-10 production with decreased IRAK-1 and NF-κB/p65 nuclear translocation was observed in sorted-purified Treg cells. IL-10(+) CD4(+) CD25(+) Treg cells may respond to Der p-2 and down-regulate NF-κB/p65 expression to maintain immune tolerance during immunotherapy.

Topics: Animals; Antigens, Dermatophagoides; Arthropod Proteins; CD4 Antigens; Dermatophagoides pteronyssinus; Desensitization, Immunologic; Forkhead Transcription Factors; Gene Expression Regulation; Humans; Hypersensitivity; Immune Tolerance; Interferon Regulatory Factor-3; Interleukin-1 Receptor-Associated Kinases; Interleukin-10; Interleukin-2 Receptor alpha Subunit; Membrane Glycoproteins; NF-kappa B; Receptors, Interleukin-1; Respiratory Function Tests; Signal Transduction; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

The increasing prevalence of allergic diseases in infants and children as well as adults has become an important issue in public health in industrial countries. However, few preventive measures are available to reduce the risk of allergic diseases in infants; e.g. the avoidance of smoking and alcohol consumption during pregnancy and lactation. Therefore, there is an enthusiasm to identify certain factors in foods, nutrients, and environment responsible for the primary prevention of allergic diseases during infancy. In the last decade, TGF-beta in maternal milk has been implicated in the prevention of allergic diseases in infants and young children. This review summarizes the relevant epidemiological reports and highlights the recent animal studies to support the preventive role of orally administered TGF-beta, such as TGF-beta in human milk, in the development of allergic diseases in infants. We also provide suggestions for the potential use of dietary (oral) TGF-beta for the primary prevention of allergic diseases. Further studies to address the scientific validity and mechanistic insight to this Mother Nature-inspired concept are clearly required and will be important to develop new approaches to prevent allergic diseases.

Topics: Animals; Bottle Feeding; Female; Humans; Hypersensitivity; Infant; Mice; Milk, Human; Pregnancy; Pregnancy Complications; Probiotics; Transforming Growth Factor beta

Topics: Antigens, Plant; CD4-Positive T-Lymphocytes; Cell Proliferation; Cytokines; Humans; Hypersensitivity; Immune Tolerance; Interferon-gamma; Interleukin-10; Leukocytes, Mononuclear; Poaceae; Rhinitis, Allergic, Seasonal; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Children living on farms have fewer allergies. It is unclear whether breastfeeding in different environments contributes to preventing allergies by exposing offspring to different cytokines that can modulate immune responses. The aim of this study was to quantify and compare levels of Transforming Growth Factor-beta1 (TGF-beta1) and Interleukin-10 (IL-10) in the colostrum and mature milk of mothers living in towns at sea level (references) and mothers on farms. Milk samples were collected within 3 days postpartum (colostrum) and at the first month of the baby's life (mature milk). Sixty-nine reference mothers and 45 farm mothers participated in the study. TGF-beta1 concentrations were significantly higher both in the colostrum (p < 0.05) and in mature milk (p < 0.05) of farm mothers. In the reference mothers, a significant decrease in TGF-beta1 concentrations was observed between colostrum (650, range 0-8000 pg/ml) and mature milk (250, range 0-8000 pg/ml) (p < 0.05). In farm mothers, TGF-beta1 concentrations were 1102 pg/ml (range 0-14,500) in colostrum and remained high in mature milk (821 pg/ml, range 0-14,650). IL-10 concentrations were higher in the mature milk of farm mothers (p < 0.05). No significant differences in IL-10 were observed between colostrum and mature milk in the control group (15 pg/ml, range 0-1800, and 0 pg/ml, range 0-230) or in farm mothers (9.5 pg/ml, range 0-1775, and 14.2 pg/ml, range 0-930), respectively. Exposure to a farm environment is associated with higher concentrations of TGF-beta1 and IL-10 in breast milk when compared to exposure to an urban environment. Higher cytokine concentrations in breast milk may influence early modulation of the development of an immune response, leading to a reduced prevalence of allergy-related diseases in farm children.

Topics: Animals; Colostrum; Female; Humans; Hypersensitivity; Immunity, Maternally-Acquired; Immunomodulation; Infant; Interleukin-10; Italy; Lactation; Milk; Rural Population; Transforming Growth Factor beta; Urban Population

Intestinal bacteria trigger IgA production and delayed maturation of mucosal IgA response is linked to allergy development.. Our aim was to investigate if plasma levels of IgA or APRIL (a proliferation inducing ligand), an important factor for IgA class switch recombination, in infancy correlates with intestinal colonization by any specific bacteria or yeast. We also examined if plasma IgA or APRIL levels are related to sensitization and the development of eczema.. IgA was quantified in plasma obtained from infants at birth and at 4 and 18 months of age and APRIL was measured at 4 months of age. Colonization by major bacterial groups and yeast was followed in the first 8 weeks of life by quantitative culture of stool samples. A clinical evaluation regarding the presence of allergen-specific IgE or eczema and eosinophil counts in blood was performed at 18 months of age.. In multiple linear regression analysis, only colonization by Staphylococcus aureus strains producing toxins with superantigen function (SEA-D or TSST-1) made an independent contribution to plasma IgA levels at 4 months of age. Further, increased levels of APRIL in plasma at 4 months were negatively associated with sensitization while IgA plasma levels were inversely correlated to eczema development and blood eosinophil counts at 18 months of age.. Early intestinal colonization by toxigenic S. aureus strains seems to promote systemic IgA responses. Furthermore, high levels of APRIL and IgA in the circulation at 4 months of age seem to correlate negatively with allergy development.

Topics: Allergens; Eczema; Enterotoxins; Eosinophils; Escherichia coli; Humans; Hypersensitivity; Immunoglobulin A; Immunoglobulin E; Immunoglobulin M; Infant; Intestines; Linear Models; Staphylococcus aureus; Transforming Growth Factor beta; Tumor Necrosis Factor Ligand Superfamily Member 13

In healthy individuals, humoral immune responses to allergens consist of serum IgA and IgG4, whereas cellular immune responses are controlled by regulatory T (Treg) cells. In search of new compounds that might prevent the onset of allergies by stimulating this type of immune response, we have focused on the mucosal adjuvant, cholera toxin B (CTB), as it induces the formation of Treg cells and production of IgA. Here, we have found that CTB suppresses the potential of dendritic cells to prime for Th2 responses to inhaled allergen. When we administered CTB to the airways of naïve and allergic mice, it strongly suppressed the salient features of asthma, such as airway eosinophilia, Th2 cytokine synthesis, and bronchial hyperreactivity. This beneficial effect was only transferable to other mice by transfer of B but not of T lymphocytes. CTB caused a transforming growth factor-beta-dependent rise in antigen-specific IgA in the airway luminal secretions, which was necessary for its preventive and curative effect, as all effects of CTB were abrogated in mice lacking the luminal IgA transporting polymeric Ig receptor. Not only do these findings show a novel therapeutic avenue for allergy, they also help to explain the complex relationship between IgA levels and risk of developing allergy in humans.

Topics: Adjuvants, Immunologic; Adoptive Transfer; Allergens; Animals; B-Lymphocytes; Cholera Toxin; Cytokines; Dendritic Cells; Disease Models, Animal; Female; Hypersensitivity; Immunoglobulin A, Secretory; Mice; Mice, Inbred BALB C; Ovalbumin; T-Lymphocytes, Regulatory; Th2 Cells; Transforming Growth Factor beta

Allergens can be maternally transferred to the fetus or neonate, though it is uncertain how this initial allergen exposure may impact the development of allergy responses. To evaluate the roles of timing and level of maternal allergen exposure in the early life sensitization of progeny, female BALB/c mice were given ovalbumin (OVA) orally during pregnancy, lactation or weekly at each stage to investigate the immunoglobulin E (IgE) antibody production and cellular responsiveness of their offspring. Exposure to OVA during pregnancy was also evaluated in OVA-specific T-cell receptor (TCR) transgenic (DO11.10) mice. The effect of prenatal antigen exposure on offspring sensitization was dependent on antigen intake, with low-dose OVA inducing tolerance followed by neonatal immunization that was sustained even when pups were immunized when 3 weeks old. These offspring received high levels of transforming growth factor-beta via breastfeeding. High-dose exposure during the first week of pregnancy or perinatal period induced transient inhibition of IgE production following neonatal immunization; although for later immunization IgE production was enhanced in these offspring. Postnatal maternal antigen exposure provided OVA transference via breastfeeding, which consequently induced increased offspring susceptibility to IgE antibody production according to week post-birth. The effect of low-dose maternal exposure during pregnancy was further evaluated using OVA transgenic TCR dams as a model. These progeny presented pronounced entry of CD4(+) T cells into the S phase of the cell cycle with a skewed T helper type 2 response early in life, revealing the occurrence of allergen priming in utero. The balance between tolerance and sensitization depended on the amount and timing of maternal allergen intake during pregnancy.

Topics: Administration, Oral; Allergens; Animals; CD4-Positive T-Lymphocytes; Cytokines; Female; Hypersensitivity; Immune Tolerance; Immunoglobulin E; Male; Maternal Exposure; Maternal-Fetal Exchange; Mice; Mice, Inbred BALB C; Mice, Transgenic; Ovalbumin; Pregnancy; Receptors, Antigen, T-Cell; Transforming Growth Factor beta

To determine transforming growth factor (TGF) beta(1), interleukin (IL) 4, and IL-10 concentrations in human milk and to assess the relationship between allergic disorders in mothers and the content of the interleukins in their milk.. Thirty allergic and 46 healthy mothers were included in the study. Colostrum was collected 2-3 days after delivery. Cytokine concentrations were determined with commercial enzyme-linked immunosorbent systems.. TGF-beta(1)was found in milk from 23 women in the control group (53.49%) and 11 in the allergy group (37.93%). When TGF-beta(1) was present, the median concentration was higher in the allergy group than in the control (61.5 and 30.4 pg/mL, respectively; P < 0.004). IL-10 was present in the colostrum of all the women and the median IL-10 concentration did not differ between the allergy (50.5 pg/mL) and control (51.5 pg/mL) groups. The probability of occurrence of a positive IL-4 value in the allergy group was greater than in the control group (chi-squared [df=1] = 2.60, P < 0.053). Median IL-4 level did not differ significantly between the two groups (0.5 and 0.5 pg/mL respectively).. TGF-beta(1) was detected less often in the colostrum of allergic mothers than in that of mothers without allergy (but the difference was not statistically significant). IL-4 was found more often in the colostrum of allergic mothers than nonallergic ones. The allergy status did not correlate with IL-10 concentration.

Topics: Adult; Colostrum; Enzyme-Linked Immunosorbent Assay; Female; Humans; Hypersensitivity; Interleukin-10; Interleukin-4; Middle Aged; Transforming Growth Factor beta; Young Adult

Exosomes are nanovesicles originating from multivesicular bodies that are secreted by a variety of cell types. The dual capability of exosomes to promote immunity or to induce tolerance has prompted their clinical use as vehicles for vaccination against different human diseases. In the present study, the effect of allergen-specific exosomes from tolerized mice on the development of allergen-induced allergic response was determined using a mouse model. Mice were tolerized by respiratory exposure to the olive pollen allergen Ole e 1. Exosome-like vesicles were isolated from bronchoalveolar lavage fluid of the animals by the well-established filtration and ultracentrifugation procedure, characterized by electron microscopy, Western blot, and FACS analyses, and assessed in a prophylactic protocol. To this end, BALB/c mice were intranasally treated with tolerogenic exosomes or naive exosomes as control, 1 wk before sensitization/challenge to Ole e 1. Blood, lungs, and spleen were collected and analyzed for immune responses. Intranasal administration of tolerogenic exosomes inhibited the development of IgE response, Th2 cytokine production, and airway inflammation--cardinal features of allergy--and maintained specific long-term protection in vivo. This protective effect was associated with a concomitant increase in the expression of the regulatory cytokine TGF-beta. These observations demonstrate that exosomes can induce tolerance and protection against allergic sensitization in mice. Thus, exosome-based vaccines could represent an alternative to conventional therapy for allergic diseases in humans.

Topics: Administration, Intranasal; Allergens; Animals; Antigens, Plant; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Female; Hypersensitivity; Immune Tolerance; Immunoglobulin E; Inflammation; Interferon-gamma; Interleukin-10; Lung; Mice; Mice, Inbred BALB C; Microscopy, Electron, Transmission; Plant Proteins; Pollen; Th2 Cells; Transforming Growth Factor beta; Transport Vesicles

Periostin is an extracellular matrix protein that has been primarily studied in the context of the heart, where it has been shown to promote cardiac repair and remodeling. In this study, we focused on the role of periostin in an allergic eosinophilic inflammatory disease (eosinophilic esophagitis (EE)) known to involve extensive tissue remodeling. Periostin was indeed markedly overexpressed (35-fold) in the esophagus of EE patients, particularly in the papillae, compared with control individuals. Periostin expression was downstream from transforming growth factor-beta and interleukin-13, as these cytokines were elevated in EE esophageal samples and markedly induced periostin production by primary esophageal fibroblasts (107- and 295-fold, respectively, at 10 ng ml(-1)). A functional role for periostin in eliciting esophageal eosinophilia was demonstrated, as periostin-null mice had a specific defect in allergen-induced eosinophil recruitment to the lungs and esophagus (66 and 72% decrease, respectively). Mechanistic analyses revealed that periostin increased (5.8-fold) eosinophil adhesion to fibronectin. As such, these findings extend the involvement of periostin to esophagitis and uncover a novel role for periostin in directly regulating leukocyte (eosinophil) accumulation in T helper type 2-associated mucosal inflammation in both mice and humans.

Topics: Animals; Asthma; Cell Adhesion; Cell Adhesion Molecules; Dermatitis, Atopic; Eosinophils; Esophagitis; Esophagus; Fibroblasts; Humans; Hypersensitivity; Interleukin-13; Lung; Mice; Mice, Knockout; Pulmonary Eosinophilia; Rhinitis; Transforming Growth Factor beta

Mucosal tolerance induction with vaccines based on peptides representing T-cell epitopes of allergens is a promising way for treating allergic diseases. Ole e 1 is the main allergen of olive pollen, which is an important cause of allergy in Mediterranean countries. The aim of this study was to evaluate the ability of the peptide T109-K130 containing a dominant T-cell epitope of Ole e 1, to modulate the allergen-specific immune response in a prophylactic mouse model. Mice were intranasally treated with the peptide 1 week prior to sensitization with Ole e 1. Blood, lungs and spleens were collected and analysed for immune response. Intranasal pretreatment of mice with the peptide led to suppress serum specific IgE, IgG1 and IgG2a antibody levels, and markedly reduced proliferative T-cell response and Th2-cytokine production, but increased IFN-gamma secretion in spleen cell cultures. Increased mRNA IL-10 levels were observed in lungs from pretreated mice. Pathologic alterations of the lung associated with airway inflammation (peribronchial/perivascular infiltrates, eosinophilia and mucus production) were significantly suppressed after pretreatment. Similar results were obtained when mice were sensitized 10 weeks after treatment. Our results demonstrate that intranasal administration of a single T-cell peptide protects mice against subsequent sensitization to the allergen, possibly via IFN-gamma and IL-10. This study emphasizes the usefulness of nasal peptide T-based vaccines against allergy.

Topics: Administration, Intranasal; Allergens; Animals; Antigens, Plant; Cell Proliferation; Epitopes, T-Lymphocyte; Female; Gene Expression Regulation; Humans; Hypersensitivity; Immune Tolerance; Immunization; Immunoglobulin E; Inflammation; Interferon-gamma; Interleukin-10; Lung; Mice; Mice, Inbred BALB C; Peptides; Plant Proteins; Pollen; Respiratory System; Time Factors; Transforming Growth Factor beta

It is now believed that both chronic airway inflammation and remodeling contribute significantly to airway dysfunction and clinical symptoms in allergic asthma. Transforming growth factor (TGF)-beta is a powerful regulator of both the tissue repair and inflammatory responses, and numerous experimental and clinical studies suggest that it may play an integral role in the pathogenesis of asthma.. We investigated the role of TGF-beta in the regulation of allergic airway inflammation and remodeling using a mouse model of house dust mite (HDM)-induced chronic allergic airway disease.. We have previously shown that intranasal administration of an HDM extract (5 d/wk for 5 wk) elicits robust Th2-polarized airway inflammation and remodeling that is associated with increased airway hyperreactivity. Here, Balb/c mice were similarly exposed to HDM and concurrently treated with a pan-specific TGF-beta neutralizing antibody.. We observed that anti-TGF-beta treatment in the context of either continuous or intermittent HDM exposure had no effect on the development of HDM-induced airway remodeling. To further confirm these findings, we also subjected SMAD3 knockout mice to 5 weeks of HDM and observed that knockout mice developed airway remodeling to the same extent as HDM-exposed littermate controls. Notably, TGF-beta neutralization exacerbated the eosinophilic infiltrate and led to increased airway hyperreactivity.. Collectively, these data suggest that TGF-beta regulates HDM-induced chronic airway inflammation but not remodeling, and furthermore, caution against the use of therapeutic strategies aimed at interfering with TGF-beta activity in the treatment of this disease.

Topics: Animals; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Eosinophils; Female; Hypersensitivity; Lung; Mice; Mice, Inbred BALB C; Mice, Knockout; Pyroglyphidae; Smad3 Protein; Transforming Growth Factor beta

We have previously shown that in mice, diphtheria-tetanus-acellular pertussis (DTaP) vaccination before Bordetella pertussis infection resulted in, besides effective clearance, immediate hypersensitivity (lung eosinophilia, increased total serum immunoglobulin E [IgE], and increased ex vivo Th2 cytokine production by cells from the bronchial lymph nodes). To better appreciate the extent of these findings, we measured DTaP vaccination effects in the local lymph node assay (LLNA) and an ovalbumin (OVA) lung allergy model. In the LLNA, mice were vaccinated or adjuvant treated before being sensitized with trimellitic anhydride (TMA; inducing a Th2-directed response) and dinitrochlorobenzene (DNCB; inducing a Th1-directed response). Compared to the adjuvant-treated controls, the vaccinated mice showed a decreased response to TMA and (to a much lesser extent) an increased response to DNCB. The decreased response to TMA coincided with increased transforming growth factor beta levels. With the exception of filamentous hemagglutinin, all vaccine constituents contributed to the decreased response to TMA. In the lung allergy model, sensitization induced OVA-specific IgE, lung pathology (peribronchiolitis, perivasculitis, and hypertrophy of the bronchiolar mucus cells) and increased the number of eosinophils, lymphocytes, and neutrophils in the bronchoalveolar lavage fluid. Vaccination failed to modulate these parameters. In conclusion, although DTaP vaccination may affect the LLNA response, we found no evidence of an effect on lung allergy.

Topics: Animals; Diphtheria-Tetanus-acellular Pertussis Vaccines; Female; Hypersensitivity; Immunoglobulin E; Local Lymph Node Assay; Lung; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Phthalic Anhydrides; Species Specificity; Transforming Growth Factor beta; Vaccination

Although many studies regarding airway remodeling in asthma have been reported, only a few studies have investigated airway remodeling in allergic rhinitis.. To determine whether repetitive allergen challenge could induce airway remodeling in the nose and evaluate the effect of steroids using a murine model of allergic rhinitis.. To develop a mouse model of airway remodeling, ovalbumin-sensitized mice were repeatedly exposed to inhaled ovalbumin administration twice a week for 1 month and 3 months. Matched control mice were challenged with phosphate-buffered saline, and the treatment group received intraperitoneal dexamethasone injection. Trichrome, periodic acid-Schiff, hematoxylin-eosin, and immunohistochemical staining against matrix metalloproteinase 9 and tissue inhibitors of metalloproteinase 1 were performed to nasal and lung tissues, and the level of transforming growth factor beta in the nasal lavage fluid was analyzed.. Repetitive ovalbumin challenge for 3 months induced circumferential peribronchial fibrosis in the lung. In the nose, subepithelial fibrosis, increased matrix metalloproteinase 9 and tissue inhibitors of metalloproteinase 1 expression, goblet cell hyperplasia, and submucous gland hypertrophy were observed compared with the control group. Features of airway remodeling were more prominent in the lung tissue. Administration of dexamethasone significantly inhibited these histologic changes.. Airway remodeling associated with long-term allergen challenge can occur in the nasal mucosa and the lung. Steroid treatment prevents airway inflammation in response to acute allergen challenge, as well as airway remodeling by long-term allergen challenge.

Topics: Allergens; Animals; Anti-Inflammatory Agents; Dexamethasone; Fibrosis; Hypersensitivity; Immunohistochemistry; Lung; Matrix Metalloproteinase 9; Mice; Mice, Inbred BALB C; Nasal Mucosa; Ovalbumin; Rhinitis; Tissue Inhibitor of Metalloproteinase-1; Transforming Growth Factor beta

Peripheral tolerance to allergens is mediated in large part by the naturally occurring lung CD4(+)CD25(+) T cells, but their effects on allergen-induced airway responsiveness have not been well defined. Intratracheal, but not i.v., administration of naive lung CD4(+)CD25(+) T cells before allergen challenge of sensitized mice, similar to the administration of the combination of rIL-10 and rTGF-beta, resulted in reduced airway hyperresponsiveness (AHR) and inflammation, lower levels of Th2 cytokines, higher levels of IL-10 and TGF-beta, and less severe lung histopathology. Significantly, CD4(+)CD25(+) T cells isolated from IL-10(-/-) mice had no effect on AHR and inflammation, but when incubated with rIL-10 before transfer, suppressed AHR, and inflammation, and was associated with elevated levels of bronchoalveolar lavage TGF-beta levels. By analogy, anti-TGF-beta treatment reduced regulatory T cell activity. These data identify naturally occurring lung CD4(+)CD25(+) T cells as capable of regulating lung allergic responses in an IL-10- and TGF-beta-dependent manner.

Topics: Animals; Female; Gene Expression Regulation; Hypersensitivity; Inflammation; Interleukin-10; Lung; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Recombinant Proteins; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Naturally occurring Foxp3(+)CD4(+)CD25(+) T cells (nTregs) isolated from lungs of naive mice regulate allergic airway hyperresponsiveness (AHR) and inflammation. Here, we demonstrate the critical requirement for engagement of MHC class I on CD4(+)CD25(+) T cells by CD8 for the functional activation of these nTregs. Suppression of allergen-induced AHR and inflammation by nTregs was abolished in mice treated with anti-CD8. Correspondingly, decreased levels of IL-10 and TGF-beta and increased levels of Th2 cytokines in bronchoalveolar lavage were detected in these treated mice. Similarly, nTregs isolated from beta2m(-/-) mice or from mice treated with anti-MHC I antibody in vitro before intratracheal transfer failed to modulate AHR or inflammation. Coculture of nTregs with CD8(+) T cells increased IL-10 and TGF-beta. Addition of anti-MHC I or anti-CD8 reduced IL-10 and TGF-beta. These results demonstrate that functional activation of nTregs requires the interaction between MHC I on CD4(+)CD25(+) T cells and CD8.

Topics: Animals; CD8-Positive T-Lymphocytes; Cells, Cultured; Female; Genes, MHC Class I; Histocompatibility Antigens Class I; Hypersensitivity; Inflammation; Interleukin-10; Interleukin-2 Receptor alpha Subunit; Lung; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Mice, Knockout; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

The aim of the studies was to identify the regulatory mechanisms that act at different levels of the ongoing immune response in BALB/c mice infected with intestinal nematode H. polygyrus. The role of TGF-beta during the course of H. polygyrus infection and an immunosuppressive action of the nematode against eosinophil response in allergic pulmonary inflammation has been studied. An attempt to identify the immunoregulatory proteins of the parasite has been performed as well. The obtained results proved: (1) for the first time the direct role of TGF-beta in the regulation of the immune response during helminth infections. Neutralization of TGF-beta in vivo increased concentration of IL-12, TNF-alpha and IL-10 in serum of infected mice and restored the control number of eosinophils in the intestinal mucosa. The mobilization of the immune response after neutralization of TGF-beta led to persistent decrease of nematode egg production and faster rejection of the worm from mouse intestine; (2) for the first time it was shown that the reduction of eosinophil number was due to the lower production of eotaxin and reduced expression of CCR3 receptor, playing an essential role in the chemotaxis of these leukocytes in Ova-related asthma; (3) significant decrease of T cell proliferation by one of the H. polygyrus protein fraction. With the use of mass spectrometry seven proteins have been identified: two heat shock proteins, disulfide isomerase, calreticulin, calumenin, fructose-bisphosphate aldolase, glyceraldehyde-3-phosphate dehydrogenase. From the bibliographic data it may be supposed that calreticulin could mediate the downregulation of lymphocytes proliferation. The fraction with calreticulin stimulated also production of specific IgE.

Topics: Animals; Disease Models, Animal; Eosinophils; Hypersensitivity; Immune Tolerance; Interleukins; Intestinal Diseases, Parasitic; Mass Spectrometry; Mice; Mice, Inbred BALB C; Nematospiroides dubius; Receptors, CCR3; Strongylida Infections; Th1 Cells; Th2 Cells; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

At present there are conflicting results from studies investigating the role of corticosteroids in inhibiting airway remodeling in asthma. We have used a mouse model to determine whether administration of corticosteroids prevents the development of allergen-induced structural features of airway remodeling. Mice treated with corticosteroids were subjected to repetitive ovalbumin (OVA) challenge for 3 mo, at which time levels of peribronchial fibrosis and the thickness of the peribronchial smooth muscle layer were assessed by immunohistology, levels of transforming growth factor (TGF)-beta1 by ELISA, and the number of alpha-smooth muscle actin+/Col-1+ peribronchial myofibroblasts by immunohistochemistry. Corticosteroids significantly reduced allergen-induced increases in peribronchial collagen deposition and levels of total lung collagen but did not reduce allergen-induced increases in the thickness of the peribronchial smooth muscle layer. Levels of lung TGF-beta1 were significantly reduced in mice treated with systemic corticosteroids, and this was associated with a significant decrease in the number of peribronchial inflammatory cells that expressed TGF-beta1, including eosinophils and mononuclear cells. Corticosteroids also significantly reduced the number of peribronchial myofibroblasts. Overall, these studies demonstrate that administration of corticosteroids significantly reduces levels of allergen-induced peribronchial fibrosis. The reduction in peribronchial fibrosis mediated by corticosteroids is likely to be due to several mechanisms including inhibition of expression of TGF-beta1, a reduction in the number of peribronchial inflammatory cells expressing TGF-beta1 (eosinophils, macrophages), as well as by corticosteroids reducing the accumulation of peribronchial myofibroblasts that contribute to collagen expression.

Topics: Actins; Adrenal Cortex Hormones; Animals; Bronchi; Bronchitis; Collagen; Fibroblasts; Fibronectins; Hypersensitivity; Immunologic Techniques; Lung; Mice; Mice, Inbred BALB C; Mucus; Muscle, Smooth; Myocytes, Smooth Muscle; Ovalbumin; Staining and Labeling; Transforming Growth Factor beta; Transforming Growth Factor beta1

Precise relationship between breastfeeding and infant allergy is poorly understood. Objective Aim was to quantify TGF-beta(1) and IL-10 in colostrum and mature milk from allergic and non-allergic mothers and to verify relationship with allergic disease development.. Mothers (13 allergics, nine controls) of 22 newborns participated to prospective study on development of children atopy. Colostrum and mature milk were assayed for TGF-beta(1) and IL-10 by ELISA. Children underwent paediatrician evaluation at 6 months of life.. Data are presented as median values and range. A significant difference in concentration of TGF-beta(1) between colostrum (330, range 0-3400 pg/mL) and mature milk (215, range 0-2400 pg/mL) was observed in samples from allergic mothers (P=0.015). In mature milk TGF-beta(1) was significantly lower in allergic (215, range 0-2400 pg/mL) than in non-allergic mothers (1059, range 0-6250 pg/mL) (P=0.015). IL-10 was weakly expressed without significant differences between allergic (4.8, range 0-42 and 9.5, range 0-42 pg/mL in colostrum and in mature milk) and non-allergic mothers (0, range 0-42 pg/mL in colostrum and 0, range 0-42 pg/mL in mature milk). After 6 months 46% infants from allergic mothers, but none from controls, presented atopic dermatitis.. TGF-beta(1) was significantly less secreted in mature milk of allergic mothers, while no difference in IL-10 was found. Particular cytokine patterns in milk could influence development of atopic diseases. Further immunological studies in this field are necessary.

Topics: Breast Feeding; Colostrum; Dermatitis, Atopic; Female; Humans; Hypersensitivity; Infant; Infant, Newborn; Interleukin-10; Milk, Human; Prospective Studies; Respiratory Sounds; Transforming Growth Factor beta

Heme oxygenase-1 (HO-1) has anti-inflammatory effects in asthma. CD4+CD25(high) regulatory T cells (Treg) are a potent immunoregulator that suppresses the immune response. We studied the effects of HO-1-mediated CD4+CD25(high) Treg on suppression of allergic airway inflammation by comparing mice treated with hemin, OVA, Sn-protoporphyrin (SnPP), and hemin plus SnPP. Airway responsiveness, airway eosinophil infiltration, the level of OVA-specific IgE, and the numbers of cells in general and eosinophils in particular in bronchial alveolar lavage fluid were lower in the hemin group than in the OVA, SnPP, and hemin plus SnPP groups. The expressions of HO-1 mRNA and protein in the lung were increased by repeated administrations of hemin and SnPP. However, the activity of HO-1 was highest in hemin mice. The percentage and suppressive function of CD4+CD25(high) Treg and the expression of Foxp3 mRNA were obviously enhanced after treatment with hemin. This increase was diminished by the administration of SnPP. The concentration of serum IL-10 was higher in the hemin group than in the other groups, whereas the level of serum TGF-beta did not significantly differ across groups. Furthermore, the ratio of IFN-gamma/IL-4 mRNA in the lung was higher in hemin-treated mice than in OVA and SnPP mice. The suppressive capacity of CD4+CD25(high) Treg was not enhanced in the IL-10-deficient mice treated with hemin. In conclusion, our experiments in the animal model demonstrated that HO-1 has anti-inflammatory effects, probably via enhancement of the secretion of IL-10 and promotion of the percentage of CD4+CD25(high) Treg.

Topics: Animals; Asthma; CD4 Antigens; Disease Models, Animal; Eosinophils; Female; Forkhead Transcription Factors; Heme Oxygenase-1; Hemin; Hypersensitivity; Immunoglobulin E; Inflammation; Interferon-gamma; Interleukin-10; Interleukin-2 Receptor alpha Subunit; Interleukin-4; Lung; Metalloporphyrins; Mice; Mice, Inbred BALB C; Ovalbumin; Protoporphyrins; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

In grass pollen-allergic individuals, T cell anergy can be induced by IL-10-treated dendritic cells (IL-10-DC) resulting in the suppression of T helper type 1 (Th1) as well as Th2 cells. This study was performed to analyse whether such IL-10-DC-treated T cells are able to act as regulatory T cells (Treg) suppressing the function of other T cells in the periphery. As transforming growth factor (TGF)-beta is also a potential inducer of Treg, we additionally analysed the inhibitory capacity of TGF-beta-treated T cells in this system.. Freshly isolated CD4+ or CD4+ CD25- T cells from grass pollen-allergic donors were stimulated with autologous mature monocyte-derived allergen-pulsed DC in the presence or absence of T cells previously cultured with IL-10-DC- and/or TGF-beta.. Anergic T cells induced by allergen-pulsed IL-10-treated DC or allergen-pulsed DC and TGF-beta enhanced IL-10 production and strongly inhibited IFN-gamma production of freshly prepared peripheral CD4+ or CD4+ CD25- T cells while proliferation and Th2 cytokine production were only slightly reduced. The combination of allergen-pulsed IL-10-treated DC and TGF-beta had an additional effect leading to a significant suppression also of Th2 cytokine production and proliferation. Suppression was not antigen-specific and was mainly mediated by cell-to-cell contact and by the molecule-programmed death-1 and only partially by CTLA-4, TGF-beta and IL-10.. These data demonstrate that regulatory T cells that also suppress Th2 cytokine production are induced by two signals: TGF-beta and IL-10-DC. This is of importance for the regulation of allergic immune responses and might be exploited for future therapeutic strategies for allergic diseases.

Topics: Allergens; Antigens, CD; Antigens, Differentiation; Cell Communication; Cell Proliferation; Cells, Cultured; CTLA-4 Antigen; Dendritic Cells; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Humans; Hypersensitivity; Immunization; Interferon-gamma; Interleukin-10; Interleukin-4; Interleukin-5; Poaceae; Pollen; T-Lymphocytes, Regulatory; Th2 Cells; Transforming Growth Factor beta

The aim of this study was to ascertain factors that might be protective of the appearance of gross blood in the stools of breast-fed infants.. Logistic regression models were formed to search for variables possibly explaining the condition. In addition to the analyzed breast milk factors, mother's allergic disease was introduced into the models to control for its possible confounding effect. The breast milk samples, collected from mothers of infants with gross blood in stools (n = 23) and from mothers of healthy age-matched infants (n = 71), were analyzed for concentrations of transforming growth factor-beta2, tumor necrosis factor-alpha, interleukin (IL)-4, IL-10, prostaglandin (PG)E2, cysteinyl leukotrienes (Cys-LTs) and fatty acid composition.. Increase in the concentrations of PGE2 and Cys-LTs in the breast milk together with mother's allergic disease reduced the likelihood of gross blood in stools in the breast-fed infant. The results suggest that no single factor, but a combination of immunomodulatory factors may protect the child from gross blood in the stools of breast-fed infants. Allergic disease was not a risk factor as mother's allergic disease appeared to counterbalance the gross blood in stools. Due to the preliminary nature of the study, the results need to be verified in a larger setting. The challenge for the future lies in identifying of such active compounds for dietary modification to enforce particularly the properties of the breast milk which are immunoprotective for the infant and to reduce the likelihood of intestinal disorders in at risk infants.

Topics: Blood; Breast Feeding; Colitis; Cysteine; Dinoprostone; Fatty Acids; Feces; Female; Humans; Hypersensitivity; Immunoglobulin E; Infant; Infant, Newborn; Leukotrienes; Lipids; Logistic Models; Male; Milk, Human; Transforming Growth Factor beta; Transforming Growth Factor beta2; Tumor Necrosis Factor-alpha

The immunologic relationship between T(H)1-type autoimmune disorders and T(H)2-type allergic disorders and the role of T-cell regulation in humans is as yet unclear. The regulatory cytokine production capacity of individuals with concomitant allergy and T(H)1-type autoimmunity may provide insight into the role of T-cell regulation in both disorders.. To examine the production capacity of interleukin 10 (IL-10) and transforming growth factor beta (TGF-beta), 2 regulatory cytokines, in individuals with concomitant allergic rhinitis and T(H)1-type autoimmune diagnoses and to compare that capacity with that in individuals with allergic rhinitis only and individuals with neither diagnosis.. Seventeen case subjects and 17 age-, sex-, and ethnicity-matched controls with allergic rhinitis only were recruited from an allergy clinic. Fourteen matched controls with neither diagnosis were recruited from the general population. Peripheral blood mononuclear cells were obtained and cultured with and without mitogen stimulation (lipopolysaccharide and phytohemagglutinin). Cytokine levels from culture supernatants were measured by enzyme-linked immunosorbent assay.. Cases with allergic rhinitis and autoimmune diseases had significantly lower unstimulated day 3 IL-10 levels compared with controls with allergic rhinitis only (P = .05) and significantly lower stimulated day 5 TGF-beta levels compared with controls with neither diagnosis (P = .02). Cases had consistently lower regulatory capacity compared with both control groups, as measured by an additive index using IL-10 and TGF-beta levels.. Individuals with concomitant allergic rhinitis and T(H)1-type autoimmune disorders have a lower regulatory cytokine production capacity than individuals with allergic rhinitis only and those with neither diagnosis.

Topics: Adult; Autoimmune Diseases; Enzyme-Linked Immunosorbent Assay; Female; Humans; Hypersensitivity; Interleukin-10; Leukocytes, Mononuclear; Male; Middle Aged; Skin Tests; Th1 Cells; Transforming Growth Factor beta

The hygiene hypothesis implies that the increasing prevalence of allergy in 'westernized' countries is explained by reduced bacterial exposure in early life, but the underlying mechanism remains elusive. We therefore wanted to study the effect of bacterial lipopolysaccharide (LPS) on the generation of regulatory T (T(R)) cells in neonates, and to analyze differences between neonates with allergy risk because of a family history of atopy (FH+) and controls without such hereditary risk (FH-). Cord blood mononuclear cells from the FH+ and FH- groups were stimulated with beta-lactoglobulin in the presence of LPS. T-cell phenotypes suggestive of T(R) cells [CD25+, CD25high and integrin (CD103+)], and the intracellular proliferation antigen Ki-67 were quantified by flow cytometry. Release of the immunosuppressive cytokine transforming growth factor beta1 (TGF-beta1) from its inactive complex was determined by enzyme-linked immunosorbent assay. The analyses revealed the generation of T-cell phenotypes suggestive of T(R) cells including a CD25high T-cell subset which was inversely related to T-cell proliferation (r=-0.54, p<0.05) and to activation-induced release of TGF-beta1 (r=-0.80, p<0.001). The CD25high T-cell subset tended to be impaired in the FH+ group (% of CD3+ T cells: FH+, 5.1% vs. FH-, 12.6%), and notably, the FH+ group showed a significantly reduced capacity for generation of both CD25+ (FH+, 16.2% vs. FH-, 34.9%; p<0.01) and T cells (FH+, 2.1% vs. FH-, 3.9%; p<0.05). Our findings suggested that early-life exposure to a dietary antigen in the presence of LPS might modulate the immune system by generating T(R) cells. This capacity was impaired in neonates with hereditary allergy risk, but clinical follow-up will be required to determine a possible effect on allergy emergence.

Topics: Enzyme-Linked Immunosorbent Assay; Female; Fetal Blood; Flow Cytometry; Genetic Predisposition to Disease; Humans; Hypersensitivity; Infant, Newborn; Lipopolysaccharides; Pregnancy; Receptors, Interleukin-2; T-Lymphocyte Subsets; Transforming Growth Factor beta; Transforming Growth Factor beta1

The amniotic membrane (AM), which is the innermost layer of the placenta, was shown to possess anti-inflammatory and anti-fibrotic properties in various in vitro and clinical studies.. To evaluate the anti-fibrotic and anti-inflammatory effects of the AM matrix (AMM) on human conjunctival and lung fibroblasts in an in vitro system that tests fibrotic and inflammatory responses at the effector stages of allergic inflammation.. Human conjunctival or lung fibroblasts were seeded on plastic or on the stromal aspect of the AM, which was mounted on plastic inserts. Sonicates of human peripheral blood eosinophils activated with lipopolysaccharide (LPS), or human mast cell (HMC-1) leukaemia cell sonicates, were added to sub-confluent fibroblast monolayers. Proliferation of the sub-confluent fibroblasts was assessed using the [3H]-thymidine incorporation assay. The production of transforming growth factor (TGF)-beta1, granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-8 in conjunctival or lung fibroblasts was measured in conditioned media from these cultures by ELISA.. After 4 days in culture, the [3H]-thymidine incorporation assay indicated a reduced proliferation of activated conjunctival and lung fibroblasts when cultured directly on the AMM. The production of both TGF-beta1 and IL-8 was significantly suppressed in activated conjunctival fibroblasts cultured on the AMM compared with those cultured on plastic, while the production of both TGF-beta1 and GM-CSF was decreased in human lung fibroblast cultured on the AMM.. The AMM is capable of suppressing fibrotic responses in an in vitro system of effector stages of ocular allergic inflammation. These data may provide a basis for exploring matrix components in the AM for the treatment of allergic eye disease.

Topics: Amnion; Cell Adhesion; Cell Division; Cell Survival; Cells, Cultured; Conjunctiva; Down-Regulation; Eosinophils; Fibroblasts; Fibrosis; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Hypersensitivity; Inflammation; Interleukin-8; Lung; Mast Cells; Transforming Growth Factor beta

Specific immunotherapy is less effective in patients with multiple allergic sensitizations compared with monosensitized patients.. We therefore established a mouse model of polysensitization to the major birch and timothy grass pollen allergens to test whether allergic polysensitization can be prevented by multiple allergen application via the mucosal route.. Female BALB/c mice were immunized intraperitoneally with recombinant (r) Bet v 1, rPhl p 1, and rPhl p 5. For intranasal tolerance induction, a mixture of the complete allergens was compared with allergen-derived immunodominant peptides applied either as a mixture or as a synthetic hybrid peptide composed of the T-cell epitopes of the 3 allergens.. Intranasal application of the mixture of the complete allergen molecules did not prevent polysensitization to the same allergens. In contrast, pretreatment with a mixture of the immunodominant peptides or the hybrid peptide led to significantly reduced allergen-specific IgE responses in sera, IL-4 production in vitro, and suppressed airway inflammation. TGF-beta mRNA levels did not change, and IL-10 production was significantly suppressed after the pretreatment. The fact that the reduction of IL-10 was not abrogated after IL-10 receptor neutralization and that tolerance was not transferable with splenocytes indicates that the suppression of T(H)2 responses in polysensitized mice might not be mediated by immunosuppressive cytokines.. Our study demonstrates that it is possible to suppress allergic immune responses simultaneously to several clinical important allergens. Thus, mucosal coapplication of selected peptides/hybrid peptides could be the basis of a mucosal polyvalent vaccine to prevent multiple sensitivities in atopic patients.

Topics: Allergens; Amino Acid Sequence; Animals; Antigens, Plant; Cross Reactions; Epitope Mapping; Epitopes, T-Lymphocyte; Female; Hypersensitivity; Immune Tolerance; Immunization; Immunodominant Epitopes; Interleukin-10; Mice; Mice, Inbred BALB C; Molecular Sequence Data; Nasal Mucosa; Peptides; Plant Proteins; Th2 Cells; Transforming Growth Factor beta

A single nucleotide polymorphism (SNP) C-509T within the tumor growth factor beta1 (TGFbeta1) gene has been associated with atopic asthma and asthma severity. To further understand the mechanisms involved, the association of C-509T with allergy, T-lymphocyte proliferation and plasma TGFbeta1 concentration has been explored in a case-control study with allergic and non-allergic subjects.. The recruited subjects including allergic (n = 38) and nonallergic (n = 25) participants have been genotyped for C-509T using allele discrimination assay. Association of C-509T with allergy status was examined using logistic regression analysis in both dominant and recessive models. Association of C-509T with T-cell proliferation in control and antigen-stimulated peripheral blood mononuclear cells (PBMCs), plasma TGFbeta1 and total IgE level were tested by multiple regression analysis.. Individuals with homozygous mutant TT genotype showed a higher risk of allergy (TT: odds ratio = 5.099, 95% confidence limit: 1.355-19.190, p = 0.016) after covariates were adjusted. A trend to increased plasma TGFbeta1 in subjects with T allele has been discovered. In the meantime, the T allele is associated with lower T cell proliferation in controls and maximum response to above antigens. A low T-cell proliferation is correlated with higher plasma TGFbeta1 concentration (p < 0.01). The in vitro studies confirmed the suppressing effect of TGFbeta1 on T-cell proliferation at physiological range. A significant inhibitory effect on IL-4 production was also observed.. A C to T base change in TGFbeta1 SNP C-509T has been associated with a higher risk of allergy. The mechanisms are not clear. Elevated TGFbeta1 levels associated with the C-509T polymorphism might suppress immune activation as well as Th2 cytokine production.

Topics: Alleles; Case-Control Studies; Cell Proliferation; Cytokines; Female; Humans; Hypersensitivity; Immunity, Cellular; Male; Polymorphism, Single Nucleotide; Risk Factors; T-Lymphocytes; Transforming Growth Factor beta; Transforming Growth Factor beta1; Up-Regulation

Atopic disorders have been associated with a Th-2 cytokine predominance. This study investigated Th1- and Th2-related gene expression in asthmatics, atopics and healthy individuals.. We compared Th1- and Th2-related in vivo-signals using gene expression arrays in 18 atopic asthmatics, 8 atopic non-asthmatic and 14 healthy control subjects. Purified mRNA from peripheral blood mononuclear cells was reverse-transcribed and hybridised to cDNA membranes. Group differences were assessed after standardisation with Mann-Whitney U-test.. Atopic individuals had upregulated lymphotoxin-alpha and downregulated IFNGR1. On the other hand, they had particularly high IL-4, IL-5 and IL4R levels, together with significantly upregulated IL10. Asthmatic individuals had normal Th1-gene expression, but an upregulation og Th-2 genes. Atopic individuals had high, asthmatic individuals excessively high IL12RB1-levels. No Th-2 gene was downregulated in both atopic phenotypes. The expression of IL6R correlated with the daily dose of inhaled corticosteroids.. Atopic individuals had a down regulation of key TH1- and Th2-genes, resulting in a balanced upregulation of Th-specific genes. In contrast, asthmatic subjects had normal Th1-gene expression but a constant upregulation of Th2-specific genes, leading to Th2-predominance.

Topics: Adolescent; Adult; Aged; Asthma; Down-Regulation; Female; Humans; Hypersensitivity; Interleukins; Male; Middle Aged; Oligonucleotide Array Sequence Analysis; Receptors, Cytokine; Th1 Cells; Th2 Cells; Transforming Growth Factor beta; Up-Regulation

The mechanisms by which immune responses to nonpathogenic environmental antigens lead to either allergy or nonharmful immunity are unknown. Single allergen-specific T cells constitute a very small fraction of the whole CD4+ T cell repertoire and can be isolated from the peripheral blood of humans according to their cytokine profile. Freshly purified interferon-gamma-, interleukin (IL)-4-, and IL-10-producing allergen-specific CD4+ T cells display characteristics of T helper cell (Th)1-, Th2-, and T regulatory (Tr)1-like cells, respectively. Tr1 cells consistently represent the dominant subset specific for common environmental allergens in healthy individuals; in contrast, there is a high frequency of allergen-specific IL-4-secreting T cells in allergic individuals. Tr1 cells use multiple suppressive mechanisms, IL-10 and TGF-beta as secreted cytokines, and cytotoxic T lymphocyte antigen 4 and programmed death 1 as surface molecules. Healthy and allergic individuals exhibit all three allergen-specific subsets in different proportions, indicating that a change in the dominant subset may lead to allergy development or recovery. Accordingly, blocking the suppressor activity of Tr1 cells or increasing Th2 cell frequency enhances allergen-specific Th2 cell activation ex vivo. These results indicate that the balance between allergen-specific Tr1 cells and Th2 cells may be decisive in the development of allergy.

Topics: Adult; Allergens; Antigens, CD; Antigens, Differentiation; CTLA-4 Antigen; Humans; Hypersensitivity; Interferon-gamma; Interleukin-10; Interleukin-4; T-Lymphocytes; Th2 Cells; Transforming Growth Factor beta

Serum concentrations of immunoglobulin E (IgE) in normal circumstances are kept much lower than those of other Ig isotypes to avoid allergic reactions. B cells lacking Id2 have increased E2A activity, which leads to specific enhancement of germline transcription of the immunoglobulin epsilon locus. As a consequence, Id2-deficient B cells undergo class switch recombination (CSR) to IgE at a much higher frequency than wild-type B cells. In contrast, Id2 is induced in wild-type B cells by transforming growth factor-beta1 (TGF-beta1) and suppresses IgE CSR. Our results provide evidence for the inhibitory and selective role of Id2 in IgE CSR in response to TGF-beta1. Id2 might act as molecular safeguard to suppress IgE CSR to prevent serious complications such as allergic hypersensitivity during the normal course of immune responses.

Topics: Animals; B-Lymphocytes; Base Sequence; Basic Helix-Loop-Helix Transcription Factors; DNA; DNA-Binding Proteins; Humans; Hypersensitivity; Immunoglobulin Class Switching; Immunoglobulin E; In Vitro Techniques; Inhibitor of Differentiation Protein 2; Mice; Mice, Knockout; Promoter Regions, Genetic; Protein Binding; Repressor Proteins; Transcription Factors; Transcriptional Activation; Transforming Growth Factor beta; Transforming Growth Factor beta1

Allergic disease (AD), including atopic eczema, asthma, allergic rhinitis, and food allergy, is characterized by an imbalance between cytokines produced by distinct T-helper cell subtypes. Whether this imbalance can be transferred from mother to breast milk remains to be established. The objective was to investigate the concentrations and interactions of nutritional and inflammatory factors in breast milk. Breast milk samples were collected from mothers with AD (n = 43) and without AD (n = 51). The concentrations of transforming growth factor (TGF)-beta2, tumor necrosis factor-alpha, IL-4, IL-10, prostaglandin E2, and cysteinyl leukotrienes were measured by immunoassays and fatty acid composition by gas chromatography. Mothers with AD had a lower concentration of TGF-beta2 in breast milk [median (interquartile range), 420 (278-701) ng/L] compared with those without AD [539 (378-1108) ng/L; p = 0.003], whereas other cytokines, prostaglandin E2, and cysteinyl leukotriene concentrations or fatty acid composition were not significantly different between the groups. The breast milk inflammatory factors and fatty acid composition were shown to be related. A positive association was observed between TGF-beta2 and the proportion of polyunsaturated fatty acids (p = 0.038) and a negative association between TGF-beta2 and the proportion of saturated fatty acids (p = 0.029) in breast milk. The reduced TGF-beta2 concentration in the breast milk of mothers with AD may interfere with the development of the mucosal immune system of the breast-fed infant. The observed associations between nutritional and inflammatory factors in breast milk suggest that it may be possible to influence the immunologic properties of breast milk by dietary intervention of the mother.

Topics: Cytokines; Dinoprostone; Fatty Acids; Female; Humans; Hypersensitivity; Interleukin-10; Interleukin-4; Leukotrienes; Milk, Human; Transforming Growth Factor beta; Transforming Growth Factor beta2; Triglycerides; Tumor Necrosis Factor-alpha

Recently, it has been established that CD4(+)CD25(+) T cells with regulatory capacity are present in human peripheral blood, inhibiting allogeneic proliferation and cytokine production of preactivated CD4(+)CD25(-) respond-er T cells.. The aim of this study was to analyze in an allergen-specific setting whether such regulatory CD4(+)CD25(+) T cells also exist and function normally in atopic individuals, especially concerning the inhibition of T(H)2 cytokines.. For this purpose, CD4(+)CD25(-) or CD4(+)CD25(+) T cells from donors allergic to grass or birch pollen (mainly with rhinitis) or from healthy nonatopic donors were stimulated in the presence of autologous, mature, monocyte-derived, allergen-pulsed dendritic cells, and the preactivated CD4(+)CD25(+) T cells were added to CD4(+)CD25(-) T cells during restimulation.. CD4(+)CD25(+) T cells from the nonatopic donors and from the majority of the patients investigated proliferated poorly, produced fewer cytokines, and inhibited the proliferation and T(H)1 (IFN-gamma) and T(H)2 (IL-4 and IL-5) cytokine production of CD4(+)CD25(-) T cells but not IL-10 production. The suppression of CD4(+)CD25(-) T cells by CD4(+)CD25(+) T cells was at least partially antigen unspecific and not reversible with anti-IL-10, anti-transforming growth factor beta, or anti-cytotoxic T lymphocyte-associated antigen 4 mAb but was reversible with IL-2. In some atopic patients preactivated CD4(+)CD25(+) T cells reproducibly showed strong proliferative responses, produced higher amounts of IL-4 and IL-10 than CD4(+)CD25(-) T cells, and suppressed only the IFN-gamma production of CD4(+)CD25(-) T cells.. These data indicate that regulatory CD4(+)CD25(+) T cells are present and functional in most atopic patients with allergic rhinitis and are able to inhibit T(H)1, as well as T(H)2, cytokine production.

Topics: Abatacept; Antigens, CD; Antigens, Differentiation; CD4 Antigens; CTLA-4 Antigen; Cytokines; Humans; Hypersensitivity; Immunoconjugates; Immunophenotyping; Interleukin-10; Lymphocyte Activation; Receptors, Interleukin-2; Th1 Cells; Th2 Cells; Transforming Growth Factor beta

Oral administration of allergens can induce immune tolerance to specific allergens in rodents and hence might be a possibility to prevent and treat allergic diseases in human subjects. However, the gastrointestinal tract of mice is different from that of human subjects. The absorption of specific antigens and subsequent antigen presentation to intestinal T cells is different in both species, making it difficult to extrapolate results.. We investigated primary oral tolerance to ovalbumin (OVA) in an IgE high-responder dog model, which is more predictive for human allergic diseases than corresponding rodent models.. Oral tolerance was induced by means of a 28-day treatment with OVA dissolved in cow's milk.. We observed reduced OVA-specific IgE and IgG production in response to ensuing subcutaneous challenges. Allergic conjunctivitis induced by means of ocular and airway provocation was significantly reduced in tolerized animals compared with that seen in nontolerized control animals. In addition, eosinophilia and neutrophilia in bronchoalveolar lavage fluid and bronchoconstriction after airway allergen challenge were significantly suppressed in tolerized animals. Cytokine analysis by means of real-time PCR on bronchoalveloar fluid cells after allergen challenge revealed a high-level expression of IL-10 and transforming growth factor beta, predominantly in the CD14(+) population.. Feeding infant beagles with OVA for 4 weeks is sufficient to prevent hallmark manifestations of asthma and allergy in adult life. The mechanism of oral tolerance involved an increased expression of IL-10 and transforming growth factor beta cytokines.

Topics: Administration, Oral; Animals; Asthma; Conjunctivitis; Dogs; Hypersensitivity; Immune Tolerance; Immunoglobulin E; Immunoglobulin G; Interleukin-10; Ovalbumin; RNA, Messenger; Transforming Growth Factor beta

CD4+CD25+ regulatory T cells (Treg) are instrumental in the maintenance of immunological tolerance. One critical question is whether Treg can only be generated in the thymus or can differentiate from peripheral CD4+CD25- naive T cells. In this paper, we present novel evidence that conversion of naive peripheral CD4+CD25- T cells into anergic/suppressor cells that are CD25+, CD45RB-/low and intracellular CTLA-4+ can be achieved through costimulation with T cell receptors (TCRs) and transforming growth factor beta (TGF-beta). Although transcription factor Foxp3 has been shown recently to be associated with the development of Treg, the physiological inducers for Foxp3 gene expression remain a mystery. TGF-beta induced Foxp3 gene expression in TCR-challenged CD4+CD25- naive T cells, which mediated their transition toward a regulatory T cell phenotype with potent immunosuppressive potential. These converted anergic/suppressor cells are not only unresponsive to TCR stimulation and produce neither T helper cell 1 nor T helper cell 2 cytokines but they also express TGF-beta and inhibit normal T cell proliferation in vitro. More importantly, in an ovalbumin peptide TCR transgenic adoptive transfer model, TGF-beta-converted transgenic CD4+CD25+ suppressor cells proliferated in response to immunization and inhibited antigen-specific naive CD4+ T cell expansion in vivo. Finally, in a murine asthma model, coadministration of these TGF-beta-induced suppressor T cells prevented house dust mite-induced allergic pathogenesis in lungs.

Topics: Animals; CD4 Antigens; DNA-Binding Proteins; Forkhead Transcription Factors; Gene Expression Regulation; Hypersensitivity; Immune Tolerance; Immunophenotyping; Interleukin-2; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mites; Ovalbumin; Receptors, Antigen, T-Cell; Receptors, Interleukin-2; T-Lymphocytes; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Changes in the levels of transforming growth factor (TGF)-beta cytokines or receptors observed during the progression of several inflammatory and fibrotic disorders have been used to implicate these cytokines in the pathophysiology of these diseases. Although correlative, these studies were inconclusive because they were unable to demonstrate actual continuous TGF-beta-mediated signaling in the involved tissues. We reasoned that the phosphorylation state and subcellular localization of Smad2, the intracellular effector of TGF-beta/activin-mediated signaling, could be used as a marker of active signaling mediated by these cytokines in situ. We therefore used an experimental model of ovalbumin-induced allergic airway inflammation and were able to demonstrate a dramatic increase in the numbers of bronchial epithelial, alveolar, and infiltrating inflammatory cells expressing nuclear phosphorylated Smad2 within the allergen-challenged lungs. This was accompanied by strong upregulation of the activin receptor ALK-4/ActR-IB and redistribution of the TGF-beta responsive ALK-5/TbetaR-I. Although levels of TGF-beta1, TGF-beta2, and TGF-beta3 messenger RNA (mRNA) were marginally altered, the level of activin mRNA was strongly upregulated during the inflammatory response. Our data illustrate the usefulness of antiphosphorylated Smad antibodies in demonstrating active TGF- beta/activin-mediated signaling in vivo and strongly suggest that activin/Smad-mediated signaling could be a critical contributor in the pathophysiology of allergic pulmonary diseases.

Topics: Activins; Animals; Base Sequence; Blotting, Western; Bronchitis; DNA Primers; DNA-Binding Proteins; Female; Hypersensitivity; Immunohistochemistry; Inhibins; Mice; Mice, Inbred BALB C; Phosphorylation; Protein Transport; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Smad2 Protein; Trans-Activators; Transforming Growth Factor beta

Diesel exhaust particles (DEP) are known to modulate the production of cytokines associated with acute and chronic respiratory symptoms and allergic respiratory disease. Tolerance is an important mechanism through which the immune system can maintain nonresponsiveness to common environmental antigens. We examined the effect of DEP on IL-10 and TGF-beta, cytokines produced by macrophages and repressor (Tr-like) lymphocytes which influence tolerance. Human PBMCs (n = 22) were incubated with 1-100 ng/ml of DEP, and suboptimally primed with LPS. IL-10 gene expression was assessed by the S1 nuclease protection assay, and production of IL-10, TGF-beta, TNF-alpha, IL-1 beta and IL-4 stimulated CD23 was evaluated by ELISA after 24 and 48 h. The effect of the order of exposure to DEP and LPS was evaluated on IL-10 protein and mRNA in cells (1) preincubated with LPS followed by DEP, or (2) exposed first to DEP followed by LPS. IL-10 was further evaluated using benzo[a]pyrene and [alpha]naphthoflavone as a surrogate for the polyaromatic hydrocarbons (PAHs) adsorbed to DEP. Control cells were incubated with carbon black, without PAHs. In PBMCs exposed to DEP with LPS, or preincubated with LPS before DEP, IL-10 production and mRNA fall significantly. TGF-beta is similarly suppressed, IL-1 beta secretion is significantly stimulated, and IL-4 stimulated CD23 release rises in the atopic subjects. In contrast, when DEP is added prior to LPS, IL-10 production rises, and IL-1 beta falls to zero. These effects on IL-10 are reproduced with benzo[a]pyrene and reversed by the coaddition of [alpha]naphthoflavone, its known antagonist. The carbon black fraction has no effect on IL-10 production. The effect of DEP on IL-10 can be inhibitory or stimulatory, depending on the order of exposure to DEP and LPS. Pro-inflammatory cytokines and factors rise when IL-10 is inhibited, and are suppressed when IL-10 is stimulated. These results are duplicated with benzo[a]pyrene, suggesting that the PAH portion of the DEP is the active agent.

Topics: Adult; Benzo(a)pyrene; Benzoflavones; Bronchial Hyperreactivity; Carbon; Gene Expression; Humans; Hypersensitivity; In Vitro Techniques; Interleukin-1; Interleukin-10; Interleukin-4; Leukocytes, Mononuclear; Lipopolysaccharides; Lymphocytes; Macrophages; Middle Aged; Receptors, IgE; RNA, Messenger; Transforming Growth Factor beta; Vehicle Emissions

We examined the effect of airway inflammation on airway remodeling and bronchial responsiveness in a mouse model of allergic asthma.. BALB/c mice were sensitized to ovalbumin (OA), and exposed to aerosolized OA (0.01, 0.1 and 1%). Twenty-four hours after the final antigen challenge, bronchial responsiveness was measured, and bronchoalveolar lavage (BAL) and histological examinations were carried out.. Repeated antigen exposure induced airway inflammation, IgE/IgG1 responses, epithelial changes, collagen deposition in the lungs, subepithelial fibrosis associated with increases in the amount of transforming growth factor (TGF)-beta1 in BAL fluid (BALF), and bronchial hyperresponsiveness to acetylcholine. The number of eosinophils in BALF was significantly correlated with TGF-beta1 production in BALF and the amount of hydroxyproline. Furthermore, significant correlations were found between these fibrogenic parameters and the bronchial responsiveness.. These findings demonstrated that in this murine model airway eosinophilic inflammation is responsible for the development of airway remodeling as well as bronchial hyperresponsiveness in allergic bronchial asthma.

Topics: Acetylcholine; Allergens; Animals; Asthma; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Collagen; Cytokines; Epithelial Cells; Female; Hydroxyproline; Hypersensitivity; Immunoglobulin E; Immunoglobulin G; Immunoglobulins; Lung; Mice; Mice, Inbred BALB C; Respiratory System; Transforming Growth Factor beta

Interleukin-10 (IL-10) and transforming growth factor beta (TGF-beta) are inhibitory for B and T cells, IgE production, and mast cell proliferation, and they induce apoptosis in eosinophils. These cytokines are therefore candidate genes which could contribute to the development of asthma or allergies. We investigated the hypothesis that polymorphic nucleotides within the IL-10 and TGF-beta gene promoters would link to the expression of allergies and asthma. DNA taken from families with an asthmatic proband was examined for base exchanges by single-stranded conformational polymorphism (SSCP). We demonstrated the presence of a polymorphism in the promoter region of the IL-10 gene and four in the TGF-beta gene promoters (3 in TGF-beta1 and 1 in TGF-beta2). The IL-10 gene polymorphism was a C-to-A exchange 571 base pairs upstream from the translation start site and was present between consensus binding sequences for Sp1 and elevated total serum. This polymorphism was associated with elevated total serum IgE in subjects heterozygotic or homozygotic for this base exchange (p < 0.009). The base exchange at -509 (from the transcription initiation site) in the TGF-beta promoter also linked to elevated total IgE (p < 0.01). This polymorphism represented a C-to-T base exchange which induced a YY1 consensus sequence and is present in a region of the promoter associated with negative transcription regulation.

Topics: Adenine; Apoptosis; Asthma; B-Lymphocytes; Base Pairing; Base Sequence; Cell Division; Child; Child, Preschool; Consensus Sequence; Cytosine; Eosinophils; Gene Expression Regulation; Humans; Hypersensitivity; Immunoglobulin E; Interleukin-10; Mast Cells; Polymorphism, Genetic; Polymorphism, Single-Stranded Conformational; Promoter Regions, Genetic; Protein Biosynthesis; Sp1 Transcription Factor; T-Lymphocytes; Thymine; Transforming Growth Factor beta

To assess possible triggers and cofactors for chronic fatigue syndrome (CFS) and to compare levels of selected cytokines between cases and an appropriately matched control group.. We conducted a case-control study of 47 cases of CFS obtained through a regional CFS research program maintained at a tertiary care medical center. One age-, gender-, and neighborhood-matched control was identified for each case through systematic community telephone sampling. Standardized questionnaires were administered to cases and controls. Sera were assayed for transforming growth factor-beta (TGF-beta), interleukin-1 beta, interleukin-6, tumor necrosis factor-alpha, and antibody to Borrelia burgdorferi and Babesia microti.. Cases were more likely to have exercised regularly before illness onset than controls (67% versus 40%; matched odds ratio (MOR) = 3.4; 95% CI = 1.2 to 11.8; P = 0.02). Female cases were more likely to be nulliparous prior to onset of CFS than controls (51% versus 31%; MOR = 8.0; 95% CI = 1.03 to 170; P = 0.05). History of other major factors, including silicone-gel breast implants (one female case and one female control), pre-morbid history of depression (15% of cases, 11% of controls) and history of allergies (66% of cases, 51% of controls) were similar for cases and controls. However, cases were more likely to have a diagnosis of depression subsequent to their diagnosis of CFS compared to a similar time frame for controls (MOR = undefined; 95% CI lower bound = 2.5; P < 0.001). Positive antibody titers to B burgdorferi (one case and one control) and B microti (zero cases and two controls) were also similar.. Further investigation into the role of prior routine exercise as a cofactor for CFS is warranted. This study supports the concurrence of CFS and depression, although pre-morbid history of depression was similar for both groups.

Topics: Adolescent; Adult; Aged; Animals; Antibodies, Bacterial; Antibodies, Protozoan; Babesia; Borrelia burgdorferi Group; Case-Control Studies; Data Interpretation, Statistical; Depression; Fatigue Syndrome, Chronic; Female; Humans; Hypersensitivity; Interleukin-1; Interleukin-6; Male; Middle Aged; Parity; Physical Exertion; Risk Factors; Surveys and Questionnaires; Time Factors; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

The effects of transforming growth factor (TGF) beta 1 on cytokine-enhanced eosinophil survival and degranulation were investigated in vitro to determine whether it is an inhibitory regulator of allergic inflammation. Peripheral blood eosinophils purified by Percoll density gradient centrifugation and the CD16 negative selection technique were incubated in the presence of eosinophil-activating cytokines (interleukin-5 (IL-5), IL-3, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon (IFN)-gamma) with and without TFG-beta 1 for 1-3 days. On day 1, eosinophil protein X release was measured by radioimmunoassay. Eosinophil viability on day 3 was determined by staining the cells with fluorescein diacetate and propidium iodide, and on the same day DNA was extracted and subjected to gel electrophoresis to test for fragmentation. TGF-beta 1 significantly inhibited eosinophil survival enhanced by IL-5, IL-3, GM-CSF and IFN-gamma in a dose-dependent manner. The inhibitory effects of TGF-beta 1 on IL-5-enhanced survival was partially reversed by high concentrations of IL-5 and was completely neutralized with anti-TGF-beta antibody. IL-5 inhibited DNA fragmentation of eosinophils in vitro. TGF-beta reversed the effect of IL-5, indicating that TGF-beta 1 activates the pathway of apoptosis. TGF-beta 1 significantly suppressed eosinophil protein X release induced by IL-5. These results suggest that TGF-beta 1 may play a role in the modulation of allergic inflammation.

Topics: Apoptosis; Blood Proteins; Cell Degranulation; Cell Survival; Cytokines; Dose-Response Relationship, Drug; Eosinophil-Derived Neurotoxin; Eosinophils; Humans; Hypersensitivity; In Vitro Techniques; Interleukin-5; Ribonucleases; Transforming Growth Factor beta

Hematopoietins, interleukin (IL)-3, IL-5, and granulocyte/macrophage colony-stimulating factor (GM-CSF) have previously been shown to prolong eosinophil survival and abrogate apoptosis. The objective of this study was to investigate the effect of transforming growth factor beta (TGF-beta) on eosinophil survival and apoptosis. Eosinophils from peripheral blood of mildly eosinophilic donors were isolated to > 97% purity using discontinuous Percoll density gradient. Eosinophils were cultured with hematopoietins with or without TGF-beta for 4 d and their viability was assessed. We confirmed previous observations that hematopoietins prolonged eosinophil survival and inhibited apoptosis. TGF-beta at concentrations > or = 10(-12) M abrogated the survival-prolonging effects of hematopoietins in a dose-dependent manner and induced apoptosis as determined by DNA fragmentation in agarose gels. The effect of TGF-beta was blocked by an anti-TGF-beta antibody. The anti-TGF-beta antibody also prolonged eosinophil survival on its own. The culture of eosinophils with IL-3 and GM-CSF stimulated the synthesis of GM-CSF and IL-5, respectively, suggesting an autocrine mechanism of growth factor production. TGF-beta inhibited the synthesis of GM-CSF and IL-5 by eosinophils. TGF-beta did not have any effect on the expression of GM-CSF receptors on eosinophils. We also studied the effect of TGF-beta on eosinophil function and found that TGF-beta inhibited the release of eosinophil peroxidase. Thus, TGF-beta seems to inhibit eosinophil survival and function. The inhibition of endogenous synthesis of hematopoietins may be one mechanism by which TGF-beta blocks eosinophil survival and induces apoptosis.

Topics: Antibodies, Monoclonal; Apoptosis; Cell Survival; Cells, Cultured; Eosinophilia; Eosinophils; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Cell Growth Factors; Humans; Hypersensitivity; Interleukin-3; Interleukin-5; Kinetics; Reference Values; Transforming Growth Factor beta