transforming-growth-factor-beta and Rhinitis--Allergic--Seasonal

To determine effects of probiotic consumption on clinical and immunological parameters of seasonal allergic rhinitis (SAR) in an out-of-season single nasal allergen challenge.. In a study registered at ClinicalTrials.Gov (NCT01123252), a 16-week dietary intervention was undertaken in 60 patients with allergic rhinitis (>16 years old). Using a double-blinded, placebo-controlled anonymised design, the patients were divided equally into two groups. One group was given a dairy drink containing Lactobacillus casei Shirota to ingest daily while the other consumed a similar drink without bacteria. Participants attended the clinic on two consecutive days before the intervention and then again at the end of the study period. On the first day of each 2-day visit, following clinical examination, assessments were made of total nasal symptoms scores and peak nasal inspiratory flow. Nasal scrapings, nasal lavage and blood were collected for laboratory analyses of cellular phenotypes, soluble mediator release and in vitro responses to pollen allergen. These procedures were repeated 24 hours following nasal allergen challenge.. Prior to and following intervention there were no detectable differences between study groups in measured clinical outcome. After intervention, there were differences between groups in their percentages of CD86+ epithelial cells (p = 0.0148), CD86+CD252+ non-epithelial cells (p = 0.0347), sIL-1RII release (p = 0.0289) and IL-1β (p = 0.0224) levels at the nasal mucosa. Delivery of probiotic also suppressed production of sCD23 (p = 0.0081), TGF-β (p = 0.0283) and induced increased production of IFN-γ (p = 0.0351) in supernatants of cultured peripheral blood.. This study did not show significant probiotic-associated changes with respect to the primary clinical endpoint. An absence of overt clinical benefit may be due to an inability of single nasal challenges to accurately represent natural allergen exposure. Nevertheless, oral delivery of probiotics produced changes of the immunological microenvironment at the nasal mucosa in individuals affected by SAR.. ClinicalTrials.Gov NCT01123252.

Topics: Administration, Oral; Adult; Allergens; Antigens, CD; Double-Blind Method; Female; Humans; Interferon-gamma; Interleukin-1beta; Lacticaseibacillus casei; Male; Middle Aged; Nasal Mucosa; Probiotics; Rhinitis, Allergic, Seasonal; Transforming Growth Factor beta

We have previously shown that short-course treatment with Amb a 1-immunostimulatory phosphorothioate oligonucleotide conjugate (AIC) before the ragweed season modifies the response of the nasal mucosa to allergen challenge in ragweed-sensitive patients by increasing Th1 cytokines and decreasing both Th2 cytokines and eosinophilia after the ragweed season. The effect of AIC immunotherapy on CD4+CD25+ T cell expression in the nasal mucosa is unknown.. To determine the in vivo effect of short-course AIC immunotherapy on CD4+CD25+ regulatory T cells in the nasal mucosa of ragweed-sensitive subjects.. 19 ragweed-sensitive patients with allergic rhinitis were randomly assigned to receive either 6 escalating doses of AIC (0.06-12microg; n = 12) or placebo (n = 7) at weekly intervals immediately before the 2001 ragweed season. Nasal biopsies were taken at baseline prior to immunization and again post immunization 24 hours after ragweed allergen challenge at the start and end of the ragweed season. The expression of T regulatory cells, IL-10 and TGF-beta was assessed at each time point by immunohistochemistry.. The numbers of allergen-induced CD4+-, CD4+CD25+-, IL-10- and TGF-beta-positive cells in the nasal mucosa after AIC immunization before the ragweed season did not differ between the two groups. Repeat challenge after the ragweed season led to a significant increase in CD4+CD25+ cells in AIC-compared with placebo-treated subjects. A trend toward an increase in IL-10-positive cells in the AIC-treated group did not reach statistical significance.. Short-course AIC immunotherapy increases CD4+CD25+ regulatory T cell infiltration in the nasal mucosa following allergen challenge after seasonal ragweed-pollen exposure.

Topics: Allergens; Ambrosia; Antigens, Plant; Biopsy; CD4 Antigens; Cell Count; Desensitization, Immunologic; Humans; Immunohistochemistry; Immunotherapy; Interleukin-10; Interleukin-2 Receptor alpha Subunit; Lymphocyte Activation; Nasal Mucosa; Phosphorothioate Oligonucleotides; Plant Proteins; Pollen; Rhinitis, Allergic, Seasonal; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Sublingual immunotherapy (SLIT) is safe and efficacious in the treatment of patients with allergic rhinitis. Although favorable clinical effects have been observed with controlled trials as early as a few months since the beginning of treatment, few biological changes induced by SLIT have been demonstrated.. To investigate in grass-allergic patients the effect of a 2-month SLIT regimen, administered with a simplified protocol without up-dosing, on proliferation and production of cytokines characteristic of the regulatory T-cell phenotype (interleukin 10 [IL-10] and transforming growth factor beta [TGF-beta]) by allergen-specific T cells.. Patients were recruited to the study in January 2006. SLIT was performed by self-administration and was continued for 60 days from February to April 2006. Eleven grass pollen-allergic patients with seasonal rhinitis were treated daily before the pollen season for 2 months with a modified allergen (monomeric allergoid) derived from a 3-grass pollen extract. Allergen-specific proliferation and production of IL-10 and TGF-beta were measured on peripheral blood mononuclear cells at baseline and treatment end. Tetanus toxoid served as the control antigen.. After SLIT, allergen-specific (P = .002) but not tetanus toxoid-specific proliferation decreased, whereas IL-10 transcription increased (P < .001). TGB-beta transcription was also increased after treatment, although not statistically significantly (P = .06). Changes in proliferation to allergen and in IL-10 transcription were correlated (r = -0.82, P = .003).. A short-term course of SLIT with modified allergen in grass-allergic patients is associated with the reduction of allergen-specific proliferation and with the up-regulation of the IL-10 regulatory cytokine.

Topics: Administration, Sublingual; Adult; Allergens; Allergoids; Female; Flow Cytometry; Humans; Immunotherapy; Interleukin-10; Lymphocyte Activation; Male; Middle Aged; Pilot Projects; Plant Extracts; Poaceae; Rhinitis, Allergic, Seasonal; Statistics, Nonparametric; T-Lymphocytes; Transforming Growth Factor beta

Anti-inflammatory effect of desloratadine (DL), including, but not limited to depression of production of IL-4, IL-6 and IL-8, has been shown in several in vitro experiments but only a few in vivo studies refer to this findings. The purpose of our study was to evaluate the influence of DL on levels of IL-4, IL-10, IL-18 and TGF-beta in sera of patients with seasonal allergic rhinitis (SAR). Sixty-nine subjects suffering from SAR with hypersensitivity to grass pollen were included into the evaluation of clinical efficacy of DL (5mg once daily). None of them was taking any H(1) receptor antagonist during the pollen season before inclusion into the study. Samples of peripheral blood were taken before and after 4 weeks of treatment. Levels of cytokines were determined using the ELISA method. The mean level of IL-4 was 0.212+/-0.07pg/ml before and 0.221+/-0.1pg/ml after the treatment (p=0.52); IL-10 5.13+/-3.14 and 4.71+/-0.88 (p=0.69); IL-18 54.45+/-26.09 and 44.80+/-22.42 (p=0.48); TGF beta 949.17+/-401.5 and 955.7+/-391.2 (p=0.97)pg/ml before and after the treatment, respectively. Unless in vitro DL demonstrates not only anti-allergic but also anti-inflammatory activities data from this in vivo study in a group of patients suffering from SAR do not support previous pre-clinical findings.

Topics: Adult; Drug Administration Schedule; Enzyme-Linked Immunosorbent Assay; Female; Histamine H1 Antagonists, Non-Sedating; Humans; Interleukin-10; Interleukin-18; Interleukin-4; Interleukins; Loratadine; Male; Recurrence; Rhinitis, Allergic, Seasonal; Sleep Wake Disorders; Time Factors; Transforming Growth Factor beta; Treatment Outcome

Allergen immunotherapy (IT) has long-term efficacy in IgE-mediated allergic rhinitis and asthma. IT has been shown to modify lymphocyte responses to allergen, inducing IL-10 production and IgG Abs. In contrast, a putative role for IgA and local TGF-beta-producing cells remains to be determined. In 44 patients with seasonal rhinitis/asthma, serum IgA1, IgA2, and polymeric (J chain-containing) Abs to the major allergen Phl p 5 were determined by ELISA before and after a 2-year double-blind trial of grass pollen (Phleum pratense) injection IT. Nasal TGF-beta expression was assessed by in situ hybridization. Sera from five IT patients were fractionated for functional analysis of the effects of IgA and IgG Abs on IL-10 production by blood monocytes and allergen-IgE binding to B cells. Serum Phl p 5-specific IgA2 Abs increased after a 2-year treatment (approximately 8-fold increase, p = 0.002) in contrast to IgA1. Increases in polymeric Abs to Phl p 5 (approximately 2-fold increase, p = 0.02) and in nasal TGF-beta mRNA (p = 0.05) were also observed, and TGF-beta mRNA correlated with serum Phl p 5 IgA2 (r = 0.61, p = 0.009). Post-IT IgA fractions triggered IL-10 secretion by monocytes while not inhibiting allergen-IgE binding to B cells as observed with IgG fractions. This study shows for the first time that the IgA response to IT is selective for IgA2, correlates with increased local TGF-beta expression, and induces monocyte IL-10 expression, suggesting that IgA Abs could thereby contribute to the tolerance developed in IT-treated allergic patients.

Topics: Adult; Allergens; Antibodies; Double-Blind Method; Female; Humans; Immunoglobulin A; Immunoglobulin E; Immunotherapy; Interleukin-10; Male; Middle Aged; Monocytes; Nasal Mucosa; Plant Proteins; Poaceae; Pollen; Rhinitis, Allergic, Seasonal; Transforming Growth Factor beta

During subcutaneous immunotherapy (SCIT), there is a local mucosal shift from Th2 to Th1 type cytokine predominance and downregulation of interleukin (IL)-5 and eosinophilia. According to recent studies IL-10- and transforming growth factor (TGF)-beta-induced tolerance is another key phenomenon in SCIT. Few data to date is available on mechanisms and roles of these cytokines in sublingual immunotherapy (SLIT).. This study was undertaken to analyse the allergen-induced in vitro mRNA expression of IL-4, IL-5, IL-10, TGF-beta and interferon (IFN)-gamma during SLIT in peripheral blood mononuclear cells (PBMC) of children with allergic rhinitis (AR).. Ten patients with AR undergoing pollen SLIT with a weekly dose of 200,000 SQ-U, 10 with a weekly dose of 24,000 SQ-U of glycerinated mixture of Betula verrucosa, Corylus avellana and Alnus glutinosa and 10 with placebo were included in the study. Peripheral blood mononuclear cell samples were collected and stimulated with pollen allergen extract prior to the treatment, after 1 and 2 years of the treatment. The cytokine mRNA expression was assessed using kinetic real time reverse transcription polymerase chain reaction (RT-PCR; TaqMan).. The in vitro allergen-induced mRNA expression of IL-5 by PBMC in the placebo group at 1 (P = 0.0065) and 2 (P = 0.013) years of therapy were increased in comparison with the highest dose. The expression of IL-10 mRNA was increased in the highest dose group (P = 0.0016) and the lower dose group (P = 0.034) at 2 years of therapy when compared with placebo. The change in the expression of allergen-induced TGF-beta had an inversed correlation with the change of IL-5 (r = -0.38, P = 0.036) and positive correlation with the change of IL-10 (r = 0.58, P = 0.0019).. Sublingual immunotherapy induced a dose-dependent systemic allergen-specific immunological response in children with AR. During high-dose SLIT, there was activation of regulatory cytokine IL-10 and an inhibitory effect on IL-5 expression increase that was associated with TGF-beta.

Topics: Administration, Sublingual; Adolescent; Allergens; Alnus; Betula; Cells, Cultured; Child; Child, Preschool; Corylus; Cytokines; Desensitization, Immunologic; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Immunotherapy; In Vitro Techniques; Interferon-gamma; Interleukin-10; Interleukin-4; Interleukin-5; Leukocytes, Mononuclear; Male; Pollen; Reverse Transcriptase Polymerase Chain Reaction; Rhinitis, Allergic, Seasonal; RNA, Messenger; Time Factors; Transforming Growth Factor beta

Allergic rhinitis is a growing problem worldwide. Currently the only treatment that can modify the disease is antigen-specific immunotherapy, but its mechanism of action is not fully understood.. We comprehensively investigated the role and changes of antigen-specific T cells before and after sublingual immunotherapy (SLIT) for Japanese cedar pollinosis.. We cultured peripheral blood mononuclear cells obtained both before and 1 year after initiating SLIT and used a combination of single-cell RNA sequencing and repertoire sequencing. To investigate biomarkers, we used cells from patients participating a phase 2/3 trial of SLIT tablets for Japanese cedar pollinosis and cells from outpatients with good and poor response.. Antigen-stimulated culturing after SLIT led to clonal expansion of T. The combination of single-cell RNA sequencing and repertoire analysis helped reveal part of the underlying mechanism: SLIT promotes the expression of MSC on pathogenic T

Topics: Allergens; Biomarkers; Cryptomeria; Humans; Immunologic Factors; Interleukin-2; Leukocytes, Mononuclear; Rhinitis, Allergic; Rhinitis, Allergic, Seasonal; Sublingual Immunotherapy; Transforming Growth Factor beta

Sensitization to specific olive pollen-allergens (Ole e 2 and 10) has been correlated with a clinical pattern of asthma. This study analyzes the association between several polymorphims of TNFA (G-308A, C-857T, and C-1031T), IL10 (C-571A and A-1117G), and TGFB (C-509-T) and these sensitizations. These polymorphisms were genotyped by allelic discrimination, in olive pollen-allergic patients (phenotyped for specific Ole e 2 and 10 sensitizations) and healthy controls. Levels of serum-soluble cytokines were correlated with specific genotypes and clinical phenotypes. The results showed that heterozygous TGFB C-509T genotype, besides having the lowest sera TGF- levels, was significantly increased in olive pollen-allergic patients compared with controls. According specific sensitizations, CC genotype of IL10 C-571A could be a protective factor for Ole e 2 sensitization and mainly for asthmatic Ole e 2 sensitized patients compared with asthmatic non-Ole e 2 sensitized patients (OR: 0.26, P = 0.008). In contrast, heterozygous CA genotype was increased in Ole e 2 asthmatic subjects compared to asthmatic non-Ole e 2 sensitized patients. Lastly, heterozygous TNFA G-308A genotype was associated with Ole e 10 sensitization (OR: 2.5, P = 0.04). In conclusion, these results suggest a role of TGF-β1 in olive-pollen sensitization and TNF-α and IL-10 genotypes in the asthma induced by specific olive-pollen allergens.

Topics: Adult; Antigens, Plant; Asthma; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Immunization; Immunoglobulin E; Interleukin-10; Male; Middle Aged; Olea; Plant Proteins; Polymorphism, Genetic; Rhinitis, Allergic, Seasonal; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Young Adult

Regulatory CD4+ T (Treg) cells are effective in maintaining immune tolerance.. To investigate single nucleotide polymorphisms (SNPs) of Transforming Growth Factor β-1 (TGF-β1) and Forkhead Box Protein 3 (FOXP3) genes in Iranian patients with allergic rhinitis (AR).. Variations at codons 10 and 25 of TGF-β1 and FOXP3 at positions -3279 A>C and -924 A>G were evaluated in AR patients and compared with controls. In a case-control study, 155 AR patients and 163 allergy-free controls were genotyped using polymerase chain reaction sequence-specific primer (PCR-SSP) technique.. The analysis of the frequency of these SNPs showed that the haplotype formed by FOXP3 -3279 A allele occurred significantly more frequently in patients than controls (odds ratio=1.44, 95% CI=1.312-2.66; p=0.001).. Our results suggest that polymorphism in FOXP3 gene is associated with susceptibility to AR.

Topics: Adult; Case-Control Studies; DNA Mutational Analysis; Female; Forkhead Transcription Factors; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Iran; Male; Polymorphism, Single Nucleotide; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Young Adult

Allergic rhinitis (AR) is characterized by inflammation sustained by dysregulated immune response. T-regulatory cells are involved in AR pathogenesis, mainly producing IL-10 and transforming growth factor (TGF)-beta. Indeed, there is a functional and allergen-specific defect of T-regulatory cells in AR. However, there are no data about the influence of allergen exposure on TGF-beta serum levels. Therefore, the aim of this preliminary study was to evaluate TGF-beta serum levels in patients with seasonal AR. Patients were evaluated either outside the pollen season and after 1 preseasonal sublingual immunotherapy (SLIT) course (38 subjects) or during the pollen season (57 subjects).. All patients were allergic to Parietaria and/or grasses alone. TGF-beta was measured by a commercially available kit. Symptoms, drug use and eosinophils were evaluated.Serum allergen-specific IgG and IgA levels were also measured by the ELISA method.. TGF-beta serum levels were significantly lower in patients evaluated outside the pollen season in comparison with the other 2 situations. SLIT induced the significantly highest TGF-beta serum levels. There was a significant negative relationship between TGF-beta and eosinophils in patients after SLIT. IgG and IgA levels were higher in SLIT-treated patients.. This preliminary study provides evidence that TGF-beta serum levels are significantly dependent on allergen exposure.

Topics: Administration, Sublingual; Adult; Allergens; Desensitization, Immunologic; Female; Humans; Male; Parietaria; Poaceae; Pollen; Rhinitis, Allergic, Seasonal; 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

The incidence of allergic diseases is increasing in industrialized countries and the immunological mechanisms leading to tolerance or allergy are poorly understood. Cytokines with suppressive abilities and CD4(+)CD25(+) regulatory T cells have been suggested to play a central role in allergen-specific responses. The aim was to determine whether major grass allergens induce production of suppressive cytokines in allergic and healthy subjects and to examine the inhibitory effect of these cytokines on allergic responses.. Peripheral blood mononuclear cells (PBMCs) were isolated from healthy and grass-allergic donors and stimulated with the major grass allergens Phl p 1 or Phl p 5. The effects of endogenous IL-10 and/or TGF-beta on proliferation and cytokine production were determined by use of blocking antibodies. In addition, the number of CD4(+)CD25(+) T cells and their expression of chemokine receptors were investigated by flow cytometry.. Phl p 1 and Phl p 5 induced IL-10 production, which down-regulated proliferation and cytokine production, in PBMC cultures from atopic but not from non-atopic donors. Comparable frequencies of CD4(+)CD25(+) T cells were present in PBMCs in the two groups, but fewer cells from atopic donors were CD4(+)CD25(+)CCR4(+) and more cells were CD4(+)CD25(+)CLA(+) compared to healthy donors.. Allergen-specific responses of grass allergic patients but not in non-atopic subjects are influenced by regulatory cytokines produced in response to the important allergens. Differences in CD4(+)CD25(+) T cell expression of chemokine receptors in allergic compared to non-atopic donors could suggest that the homing of CD4(+)CD25(+) T cells is important for the regulation of allergen-specific responses.

Topics: Adolescent; Adult; Aged; Allergens; Antibodies; Antigens; Antigens, Differentiation, T-Lymphocyte; Antigens, Plant; CD4 Lymphocyte Count; Cell Proliferation; Female; Humans; Immunophenotyping; Interferon-gamma; Interleukin-10; Interleukin-4; Interleukin-5; Leukocytes, Mononuclear; Male; Membrane Glycoproteins; Middle Aged; Plant Proteins; Poaceae; Receptors, CCR4; Receptors, Interleukin-10; Rhinitis, Allergic, Seasonal; T-Lymphocytes; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Tuberculin; Young Adult

Transforming growth factor-beta (TGF-beta) levels are elevated in the nasal mucosa in allergic rhinitis. However, because TGF-beta is secreted extracellulary in latent complexes, it remains unclear whether the local TGF-beta expression actually drives active signaling and affects the pathophysiology of allergic rhinitis. The objective of this study is to investigate whether TGF-beta signaling is activated in allergic rhinitis and plays a role in the pathophysiology of allergic rhinitis.. An ovabumin (OVA)-sensitized and -nasally challenged mouse model of allergic rhinitis was established and phosphorylation of Smad2 in the nasal mucosa was examined by immunohistochemistry. In addition, the effects of the pharmacological inhibition of endogenous TGF-beta signaling on the allergic rhinitis model were histologically examined. Furthermore, phosphorylation of Smad2 in the nasal mucosa samples obtained from patients with allergic rhinitis was also evaluated.. In the mouse model of allergic rhinitis, OVA challenge induced phosphorylation of Smad2 predominantly in epithelial cells in the nasal mucosa. In addition, the administration of an inhibitor of TGF-beta type I receptor kinase activity during OVA challenge suppressed goblet cell hyperplasia in the nasal mucosa. Furthermore, phosphorylated Smad2 expression increased in nasal epithelial cells in patients with allergic rhinitis.. These results suggest that TGF-beta signaling is activated in epithelial cells in the nasal mucosa in allergic rhinitis and may contribute to the development of goblet cell hyperplasia.

Topics: Animals; Cell Proliferation; Disease Models, Animal; Goblet Cells; Humans; Hyperplasia; Immunization; Mice; Nasal Mucosa; Ovalbumin; Phosphorylation; Protein Serine-Threonine Kinases; Pyrazoles; Quinolines; Receptor, Transforming Growth Factor-beta Type I; Receptors, Transforming Growth Factor beta; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal; Signal Transduction; Smad2 Protein; Transforming Growth Factor beta

Topics: Administration, Sublingual; Adult; Desensitization, Immunologic; Eosinophils; Female; Humans; Leukocyte Count; Male; Nasal Mucosa; Pollen; Rhinitis, Allergic, Seasonal; Transforming Growth Factor beta

Two new T cell subsets may be involved in allergic rhinitis (AR) pathogenesis: Th17 and T regulatory cells, mainly producing IL-17 and TGF-beta respectively. Successful Sublingual Immunotherapy (SLIT) induces relevant immunological changes, thus the aim of this study was to evaluate serum IL-17 and TGF-beta levels in AR patients treated with SLIT for 2 years. Patients' blood samples were collected before initiating SLIT (baseline), three months after the end of the first pre-seasonal SLIT course, and at the end of the second pre-seasonal course. IL-17 was detectable only in the most severe allergic patients. SLIT significantly induced an increase in serum TGF-beta levels. There was moreover a significant relationship between TGF-beta and symptom severity and drug use at the end of the study. Therefore, this study provides clinically relevant evidence that two pre-seasonal SLIT courses may significantly affect serum TGF-beta levels.

Topics: Adult; Allergens; Desensitization, Immunologic; Disease Progression; Female; Follow-Up Studies; Humans; Interleukin-17; Male; Pollen; Rhinitis, Allergic, Seasonal; Transforming Growth Factor beta

This study aimed to evaluate the effect of dexamethasone on the expression of transforming growth factor (TGF)-beta in the mouse model of allergic rhinitis.. Female BALB/c mice were randomly assigned to four groups, including two control groups and two treatment groups.. General sensitization and local challenge were performed with ovalbumin (OVA). In the treatment groups, dexamethasone was injected intraperitoneally 3 hours before general sensitization or local challenge. Symptom score, eosinophil infiltration, and immunostaining for TGF-beta1 and CD4 in nasal mucosa, and TGF-beta1 and OVA-specific immunoglobulin E (IgE) in sera were analyzed.. Dexamethasone administration before general sensitization reduced the symptom score, OVA-specific IgE, and eosinophil infiltration and increased the serum level of TGF-beta1 significantly. Dexamethasone administration before local challenge reduced only the eosinophil infiltration significantly. Immunoreactivity of TGF-beta1 and CD4 was lower in both treatment groups.. These results suggest that dexamethasone may play an important role in the regulation of allergic reactions by at least two mechanisms; one by suppressing allergic sensitization through decrease of CD4+ T cells and increase of TGF-beta, and the other by suppressing late allergic reactions through the inhibition of proliferation and chemotaxis of inflammatory cells such as eosinophils.

Topics: Animals; CD4-Positive T-Lymphocytes; Dexamethasone; Disease Models, Animal; Eosinophils; Female; Gene Expression; Glucocorticoids; Immunoglobulin E; Immunohistochemistry; Leukocyte Count; Mice; Mice, Inbred BALB C; Nasal Mucosa; Ovalbumin; Reverse Transcriptase Polymerase Chain Reaction; Rhinitis, Allergic, Seasonal; RNA, Messenger; Transforming Growth Factor beta

Mucosal tolerance induction is suggested as treatment strategy for allergic diseases. Using a murine model of birch pollen (BP) allergy we investigated the long-term efficacy and the underlying mechanisms of mucosal tolerance induction with two structurally different molecules in a prophylactic and in a therapeutic set-up.. The three-dimensional major BP allergen Bet v 1 or a nonconformational hypoallergenic fragment thereof was intranasally applied before (prophylaxis) or after sensitization (therapy).. In the prophylactic application both the Bet v 1 allergen and the fragment prevented allergic sensitization, and this effect lasted for 1 year. In the therapeutic approach established allergic immune responses were also suppressed after treatment with either of the molecules. However, a long-lasting curative effect (6 months) was only achieved with the Bet v 1 allergen but not with the Bet v 1 fragment. Real-time reverse transcriptase polymerase chain reaction (RT-PCR) analysis of splenocytes revealed that tolerance induction with the Bet v 1 allergen was associated with enhanced expression of transforming growth factor (TGF)-beta, interleukin (IL)-10, and Foxp3 mRNA in CD4+ T cells, whereas treatment with the fragment led to the induction of either Foxp3 (prophylaxis) or IL-10 (therapy) alone.. From these data we concluded (i) that the mechanisms underlying peripheral tolerance are linked to the conformation of the antigen, (ii) that mucosal tolerance is mediated by separate regulatory cell subsets, and (iii) that the long-term efficacy of immunosuppression is associated with the presence of Foxp3+ T cells.

Topics: Administration, Intranasal; Allergens; Animals; Betula; Desensitization, Immunologic; Disease Models, Animal; Epitopes, T-Lymphocyte; Female; Forkhead Transcription Factors; Immune Tolerance; Interleukin-10; Mice; Mice, Inbred BALB C; Nasal Mucosa; Peptide Fragments; Pollen; Reverse Transcriptase Polymerase Chain Reaction; Rhinitis, Allergic, Seasonal; RNA, Messenger; T-Lymphocytes; Transforming Growth Factor beta

The late-phase reaction (LPR) of the skin is an in vivo model of allergic inflammation.. We sought to identify disease-associated pathways in the LPR using a network-based analysis.. The LPR was examined by means of DNA microarray analysis of skin biopsy specimens from 10 patients with allergic rhinitis and 10 healthy control subjects. The results were further analyzed in 2 different materials consisting of nasal fluids and allergen-challenged CD4(+) T cells from patients with allergic rhinitis.. The DNA microarray analysis revealed several genes of known relevance to allergy. The eosinophil marker Charcot-Leyden crystal protein (CLC) that encodes Charcot-Leyden crystal protein differed most in expression. A network-based analysis showed upregulation of IL-4- and CCL4-dependent pathways and downregulation of a TGF-beta-induced pathway. CCL4 is expressed by CD4(+) T cells and chemotactic for eosinophils. We hypothesized that allergen induces release of CCL4 from T(H)2 cells and that this contributes to influx of eosinophils. Further analysis showed increase of CCL4 protein in nasal fluids from allergic patients during the season. Allergen challenge of PBMCs resulted in proliferation of T(H)2 cells and increased production of CCL4 in CD4(+) T cells from allergic patients. An analysis of the DNA microarray data revealed a significant correlation between CCL4 and the eosinophil marker CLC.. A network-based analysis of the LPR showed increased activity of IL-4- and CCL4- dependent pathways and downregulation of the TGF-beta-induced pathway. Allergen-induced release of CCL4 from T(H)2 cells might contribute to influx of eosinophils during the LPR.. Involvement of multiple interacting pathways indicates that it might be difficult to identify one single mediator as a biomarker or drug target in allergic inflammation.

Topics: Adult; CD4-Positive T-Lymphocytes; Chemokine CCL4; Chemokines, CC; Humans; Interleukin-4; Macrophage Inflammatory Proteins; Middle Aged; Oligonucleotide Array Sequence Analysis; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal; Signal Transduction; Skin; Transforming Growth Factor beta

Allergic rhinitis is characterized by the epithelial accumulation of cells, particularly mast cells and eosinophils. There is little information relating to the chemotaxins responsible for mast cell epithelial accumulation in this disease.. Expression of the mast cell chemoattractants TGF-beta, eotaxin, and stem cell factor and their receptors was investigated in tissue sections from biopsy specimens obtained from patients with naturally occurring allergic rhinitis.. Specific immunohistochemical staining was performed on thin sections of inferior turbinate biopsy specimens from patients with perennial and seasonal allergic rhinitis and, for comparison, from nonatopic and, where relevant, atopic healthy volunteers without rhinitis. Sequential staining of adjacent 2-microm sections was undertaken to colocalize TGF-beta receptors to mast cells.. Evidence was found of significantly increased epithelial immunoreactivity for TGF-beta1, TGF-beta2, TGF-beta3, TGF-beta receptor I, TGF-beta receptor II, and TGF-beta receptor III in patients with perennial and seasonal allergic rhinitis compared with that seen in healthy control subjects. TGF-beta receptors I and II were found to colocalize to mast cells. Eotaxin epithelial immunoreactivity was significantly increased in the perennial group, although there were no corresponding disease-related differences found in relation to CCR-3 immunoreactivity at this site. There was no increase in stem cell factor immunoreactivity within the epithelium in naturally occurring disease. Significant correlations were found between epithelial immunoreactivity for TGF-beta1, TGF-beta2, TGF-beta receptor I, TGF-beta receptor II, and the number of epithelial mast cells.. These findings of enhanced epithelial TGF-beta immunoreactivity in patients with rhinitis, the correlation with intraepithelial mast cell numbers, and the colocalization of TGF-beta receptors to mast cells suggest that the epithelial expression of TGF-beta might represent an important biologic process involved in either the recruitment or retention of mast cells within the epithelium in naturally occurring allergic rhinitis.

Topics: Adult; Chemokine CCL11; Chemokines, CC; Chemotactic Factors; Female; Humans; Male; Mast Cells; Middle Aged; Nasal Mucosa; Proto-Oncogene Proteins c-kit; Receptors, CCR3; Receptors, Chemokine; Receptors, Formyl Peptide; Receptors, Transforming Growth Factor beta; Rhinitis; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal; Stem Cell Factor; Transforming Growth Factor beta

Decreased activity of anti-inflammatory cytokines like transforming growth factor (TGF)-beta may contribute to allergic inflammation. In vivo effects of TGF-beta-effects are difficult to infer from local concentrations, since TGF-beta-effects depend on a complex system of regulatory proteins and receptors. Instead the effects of TGF-beta might be inferred by examining TGF-beta-inducible transcripts. In this study DNA microarrays were used to examine local expression of TGF-beta, TGF-beta-regulatory and -inducible transcripts in nasal biopsies from patients with symptomatic allergic rhinitis and healthy controls. In addition, nasal fluids were analysed with cytological and immunological methods. Nasal fluid eosinophils, albumin, eosinophil granulae proteins and IgE, but not TGF-beta, were higher in patients than in controls. DNA microarray analysis of nasal mucosa showed expression of transcripts encoding TGF-beta, TGF-beta-regulatory proteins and -receptors at variable levels in patients and controls. By comparison, analysis of 28 TGF-beta-inducible transcripts indicated that 23 of these had lower measurement values in patients than in controls, while one was higher, and the remaining four were absent in both patients and controls. In summary, TGF-beta and a complex system of regulatory genes and receptors are expressed in the nasal mucosa. Low expression of TGF-beta-inducible transcripts may indicate decreased TGF-beta activity in allergic rhinitis. DNA microarray analysis may be a way to study cytokine effects in vivo.

Topics: Adolescent; Adult; Biopsy; Case-Control Studies; Eosinophils; Gene Expression Regulation; Humans; Inflammation; Middle Aged; Nasal Lavage Fluid; Nasal Mucosa; Oligonucleotide Array Sequence Analysis; Oligonucleotides; Pollen; Rhinitis, Allergic, Seasonal; RNA, Complementary; RNA, Messenger; Transforming Growth Factor beta