tacrolimus and Asthma

Atopic dermatitis is a prevalent condition in children and can be effectively managed with medications such as topical calcineurin inhibitors (pimecrolimus or tacrolimus). A key unresolved safety concern is whether use of topical calcineurin inhibitors is associated with cancer. We systematically reviewed the risk of cancer in patients with atopic dermatitis exposed to topical calcineurin inhibitors.. As part of the 2022 American Academy of Allergy, Asthma and Immunology and American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters atopic dermatitis guidelines, we searched MEDLINE, Embase, the Latin American and Caribbean Health Sciences Literature database, the Índice Bibliográfico Espanhol de Ciências da Saúde database, the Global Resource of Eczema Trials database, WHO's International Clinical Trials Registry Platform, the US Food and Drug Administration database, the European Medicines Agency database, company registers, and relevant citations from inception to June 6, 2022. We included randomised controlled trials and comparative and non-comparative non-randomised studies in any language addressing cancer risk in patients with atopic dermatitis using topical calcineurin inhibitors. We excluded split-body studies and studies with less than 3 weeks of follow-up. Paired reviewers independently screened records, extracted data, and assessed risk of bias in duplicate. We used Bayesian models to estimate the probability for cancer due to topical calcineurin inhibitor exposure and the GRADE approach to determine the certainty of the evidence. Patients, advocacy groups, and care providers set a priori thresholds of important effects. This study is registered with Open Science Framework, https://osf.io/v4bfc.. We identified and analysed 110 unique studies (52 randomised controlled trials and 69 non-randomised studies [11 were non-randomised study extensions of randomised controlled trials]) including 3·4 million patients followed up for a mean of 11 months (range 0·7-120). The absolute risk of any cancer with topical calcineurin inhibitor exposure was not different from controls (absolute risk 4·70 per 1000 with topical calcineurin inhibitors vs 4·56 per 1000 without; odds ratio 1·03 [95% credible interval 0·94-1·11]; moderate certainty). For all age groups and using data from observational studies and randomised controlled trials, the use of pimecrolimus (OR 1·05 [95% credible interval 0·94-1·15]) or tacrolimus (0·99 [0·89-1·09]) is likely to have had little to no association with cancer compared with no topical calcineurin inhibitor exposure. For pimecrolimus versus tacrolimus, the finding was similar (0·95 [95% credible interval 0·83-1·07]). Findings were similar in infants, children, and adults, and robust to trial sequential, subgroup, and sensitivity analyses.. Among individuals with atopic dermatitis, moderate-certainty evidence shows that topical calcineurin inhibitors do not increase the risk of cancer. These findings support the safe use of topical calcineurin inhibitors in the optimal treatment of patients with atopic dermatitis.. American Academy of Allergy, Asthma and Immunology and American College of Allergy, Asthma and Immunology via the Joint Task Force on Practice Parameters.

Topics: Adult; Asthma; Bayes Theorem; Calcineurin Inhibitors; Child; Dermatitis, Atopic; Humans; Hypersensitivity; Infant; Neoplasms; Randomized Controlled Trials as Topic; Tacrolimus

Mast cells, the multi-functional secretory cells, are the pivotal effector cells in immune response, and contribute to the pathogenesis of many diverse diseases, like asthma and mastocytosis, by releasing numerous proinflammatory mediators. Pimecrolimus (SDZ ASM 981) is a derivative of the macrolactam ascomycin and is a member of the calcineurin inhibitor class of immunosuppressors. It inhibits the calcineurin-dependent activation of nuclear factor of activated T cells and the expression of a number of proinflammatory cytokines in turn. Pimecrolimus has high and selective anti-inflammatory activity within the skin, and with much lower potential to affect local and systemic immune responses. Therefore it has been widely used for treatment of various inflammatory skin diseases. It has a cellselective mode of action, and mast cells are its specific target cells. Pimecrolimus inhibits the release of both preformed and de novo synthesized mediators from activated mast cells and inhibits accumulation of mast cells by inducing apoptosis. Several experimental and clinical reports have demonstrated the successful application of pimecrolimus and other calcineurin inhibitors, such as tacrolimus and cyclosporine A, to treat mastocytosis, a spectrum of disorders characterized by mast cell hyperplasia, especially cutaneous mastocytosis. These new findings suggest that pimecrolimus and other calcineurin inhibitors may be a novel and effective therapeutic approach for mast cell-associated diseases such as asthma and mastocytosis.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Asthma; Calcineurin; Calcineurin Inhibitors; Humans; Mast Cells; Mastocytosis; Molecular Structure; Tacrolimus

The novel technologies in pulmonary drug delivery propelled the development of new strategies for pharmacological intervention in human diseases. In particular, this review will focus on pulmonary parameters which influence the delivery of inhaled therapeutics and summarize novel applications and recent innovations. The central issues of pulmonary drug application are optimal effectiveness under conditions of greatest safety. They not only depend on the properties of the drug but also feature the application vehicle and drug formulation. The optimization of the whole system (drug, formulation and vehicle) is therefore a necessary prerequisite for reliable inhaling medicines. Depending on the desired locus of drug action, the inhaled medicine has to be adjusted to particle size, concentration and chemical composition to guarantee a local or systemic drug action. Local asthma therapy represents the established concept for inhalation therapy. Due to the disease status, deposition of drugs is therefore often seen in central rather than peripheral airways. Recent developments in ultrafine therapeutic particles should therefore provide enough drug deposition even in the deeper airways. Recent approvals and interesting new therapy concepts will be discussed. Beside a pulmonary drug action there is an accumulating number of applications also for systemic drug action after pulmonary drug delivery. These involve among others inhaled insulin, glucagon-like-peptide 1 or growth hormone. But also novel therapeutic systems for gene therapy and vaccination are currently under investigation. Successful feasibility of these novel concepts will be expected in the near future.

Topics: Administration, Inhalation; Analgesics, Opioid; Anti-Asthmatic Agents; Asthma; Diabetes Mellitus; Drug Delivery Systems; Humans; Insulin; Lung; Nanoparticles; Tacrolimus; Tissue Distribution

To review epidemiologic correlations between asthma and atopic dermatitis (AD), identify common features in disease pathophysiology, and review steps involved in the development of asthma therapy guidelines to assess the appropriateness of a similar process and approach for AD.. A 7-member panel representing specialists in dermatology, allergy, asthma, immunology, and pediatrics from around the United States convened to review the current literature and evolving data on AD. Participants presented reviews to the panel on the epidemiology of asthma and AD, the genetic predisposition to allergic disease, the current understanding of the immunopathophysiology of AD, interrelationships between the pathologic pathways of asthma and AD, evolving treatment concepts and options in AD, and the applicability of the asthma treatment model and how it may be adapted for guideline development for AD. Commentary and criticism were recorded for use in document preparation.. There are clear epidemiologic parallels in asthma and AD. Importantly, AD frequently is the first manifestation of an atopic diathesis, which occurs in genetically predisposed individuals and also includes asthma and allergic rhinitis. Up to 80% of children with AD will eventually develop allergic rhinitis or asthma later in childhood. This classic "atopic triad" has numerous pathophysiologic elements in common, including cyclic nucleotide regulatory abnormalities, immune cell alterations, and inflammatory mediators and allergic triggers. New therapeutic options that target underlying immune mechanisms are available, and their place among treatments for AD is becoming established. Guidelines of care have been developed for asthma. The panel noted that the National Institutes of Health/National Heart, Lung, and Blood Institute guidelines for diagnosis and management of asthma, first issued in 1991, had a tremendous positive impact on many aspects of asthma treatment. It not only created a heightened awareness that asthma is a disease of chronic inflammation, but it also provided unified approaches for therapy and opened new areas of basic science and clinical research. In addition, the guidelines spurred interactions among physicians of various specialties and stimulated a great quantity of research in asthma therapy. It is anticipated that AD therapy guidelines would have similar positive outcomes.. The panel concluded that, on the basis of current information and evolving therapeutic options, a clear rationale exists to support AD guideline development. The many parallels between AD and asthma suggest that processes and approaches used for the asthma therapy guidelines would be appropriate for AD.

Topics: Administration, Topical; Adolescent; Adrenal Cortex Hormones; Adult; Anti-Inflammatory Agents; Asthma; Child; Child, Preschool; Comorbidity; Dermatitis, Atopic; Glucocorticoids; Humans; Infant; Practice Guidelines as Topic; Tacrolimus; United States

The incidence of atopic diseases, including atopic dermatitis, allergic rhinitis, and asthma, has increased in developed countries over the past several decades. These diseases comprise a large component of general pediatric practice. This review will highlight some of the recent advances in understanding the pathogenesis and natural history of these diseases, as well as the current approaches to the treatment of children with atopic diseases.. Recent studies have identified multiple risk factors for the development and progression of atopic diseases. As a result, much research is focused on identifying therapies that can be initiated at a young age to prevent disease progression. New treatment options have become available in recent years, such as topical immunomodulators for atopic dermatitis, leukotriene antagonists for seasonal allergic rhinitis, and alpha-immunoglobulin E therapy for asthma. The importance of viewing allergic rhinitis and asthma as disorders of a single airway has been emphasized. Finally, an update on the national asthma guidelines was recently released in an effort to promote optimal asthma care.. This review summarizes many of the recent advances in the diagnosis and treatment of atopic diseases in children. Although not intended to be a comprehensive review of this broad field, it provides a framework for appreciating the complexity of these diseases and for effectively managing them.

Topics: Acetates; Adrenergic beta-Agonists; Animals; Asthma; Child; Cyclopropanes; Dermatitis, Atopic; Environmental Exposure; Feces; Genetic Predisposition to Disease; Hepatitis A Virus Cellular Receptor 1; Hepatitis A Virus Cellular Receptor 2; Humans; Hypersensitivity, Immediate; Immunosuppressive Agents; Leukotriene Antagonists; Membrane Proteins; Mice; Quinolines; Receptors, Virus; Skin; Sulfides; T-Lymphocytes; Tacrolimus

Topics: Antibodies, Monoclonal; Antirheumatic Agents; Asthma; CD4 Antigens; Cross-Over Studies; Cyclosporine; Double-Blind Method; Humans; Immunosuppressive Agents; Methotrexate; Models, Immunological; Organogold Compounds; Randomized Controlled Trials as Topic; Sirolimus; Tacrolimus

Human mast cells and basophils play a key role in the pathogenesis of several immunological and inflammatory disorders, not only by producing inflammatory and fibrogenic mediators, but also by directly (CD40 ligand) and indirectly secreting various cytokines and chemokines. Studies carried out to evaluate the effects of drugs that modulate the release of mediators and cytokines from these cells have contributed to clarifying the biochemical mechanism by which immunological and non-immunological stimuli activate these cells. Significant differences have been documented between human mast cells and basophils as regard the pharmacological agents that modulate the release of mediators, between mast cells isolated from different anatomical sites, and between compounds of the same class of drugs. Efforts to gain insight into the biochemical events occurring during immunological activation of mast cells and basophils could lead to the identification of new biochemical targets for therapeutic interventions in several immunological disorders.

Topics: Adenylyl Cyclases; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Asthma; Basophils; CD40 Ligand; Cyclosporine; Cytokines; Enzyme Activation; Enzyme Inhibitors; Glucocorticoids; Histamine Release; Humans; Inflammation; Mast Cells; Membrane Glycoproteins; Organ Specificity; Phosphodiesterase Inhibitors; Protein Kinase C; Protein-Tyrosine Kinases; Steroids; Tacrolimus

Topics: Asthma; CD4-Positive T-Lymphocytes; Cytokines; Humans; Immunosuppressive Agents; Interleukin-5; Tacrolimus; Transcription, Genetic

Topics: Animals; Asthma; CD4-Positive T-Lymphocytes; Cyclosporine; Gene Expression; Humans; Interleukin-5; Ionomycin; Tacrolimus; Tetradecanoylphorbol Acetate; Transcription, Genetic

Atopic dermatitis is a prevalent condition in children and can be effectively managed with medications such as topical calcineurin inhibitors (pimecrolimus or tacrolimus). A key unresolved safety concern is whether use of topical calcineurin inhibitors is associated with cancer. We systematically reviewed the risk of cancer in patients with atopic dermatitis exposed to topical calcineurin inhibitors.. As part of the 2022 American Academy of Allergy, Asthma and Immunology and American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters atopic dermatitis guidelines, we searched MEDLINE, Embase, the Latin American and Caribbean Health Sciences Literature database, the Índice Bibliográfico Espanhol de Ciências da Saúde database, the Global Resource of Eczema Trials database, WHO's International Clinical Trials Registry Platform, the US Food and Drug Administration database, the European Medicines Agency database, company registers, and relevant citations from inception to June 6, 2022. We included randomised controlled trials and comparative and non-comparative non-randomised studies in any language addressing cancer risk in patients with atopic dermatitis using topical calcineurin inhibitors. We excluded split-body studies and studies with less than 3 weeks of follow-up. Paired reviewers independently screened records, extracted data, and assessed risk of bias in duplicate. We used Bayesian models to estimate the probability for cancer due to topical calcineurin inhibitor exposure and the GRADE approach to determine the certainty of the evidence. Patients, advocacy groups, and care providers set a priori thresholds of important effects. This study is registered with Open Science Framework, https://osf.io/v4bfc.. We identified and analysed 110 unique studies (52 randomised controlled trials and 69 non-randomised studies [11 were non-randomised study extensions of randomised controlled trials]) including 3·4 million patients followed up for a mean of 11 months (range 0·7-120). The absolute risk of any cancer with topical calcineurin inhibitor exposure was not different from controls (absolute risk 4·70 per 1000 with topical calcineurin inhibitors vs 4·56 per 1000 without; odds ratio 1·03 [95% credible interval 0·94-1·11]; moderate certainty). For all age groups and using data from observational studies and randomised controlled trials, the use of pimecrolimus (OR 1·05 [95% credible interval 0·94-1·15]) or tacrolimus (0·99 [0·89-1·09]) is likely to have had little to no association with cancer compared with no topical calcineurin inhibitor exposure. For pimecrolimus versus tacrolimus, the finding was similar (0·95 [95% credible interval 0·83-1·07]). Findings were similar in infants, children, and adults, and robust to trial sequential, subgroup, and sensitivity analyses.. Among individuals with atopic dermatitis, moderate-certainty evidence shows that topical calcineurin inhibitors do not increase the risk of cancer. These findings support the safe use of topical calcineurin inhibitors in the optimal treatment of patients with atopic dermatitis.. American Academy of Allergy, Asthma and Immunology and American College of Allergy, Asthma and Immunology via the Joint Task Force on Practice Parameters.

Topics: Adult; Asthma; Bayes Theorem; Calcineurin Inhibitors; Child; Dermatitis, Atopic; Humans; Hypersensitivity; Infant; Neoplasms; Randomized Controlled Trials as Topic; Tacrolimus

Atopic dermatitis (AD) is often the first step in the atopic march leading to the development of asthma or allergic rhinitis. The goal of this study was to determine whether early intervention with pimecrolimus limits the atopic march in infants with AD and to evaluate its efficacy and safety.. This was a 3-year double-blind study in which patients were randomized to pimecrolimus or vehicle and then open-label pimecrolimus for a planned further 3 years. Rescue topical corticosteroid was permitted if 3 days of study medication led to no improvement; investigators made decisions on rescue medication until week 14 and caregivers thereafter. Efficacy assessments included disease-free days, Eczema Area and Severity Index, and body surface area affected.. Infants ages 3 to 18 months with recent-onset AD (≤3 months) were observed for a mean of 2.8 years (N = 1,091). No significant differences between pimecrolimus- and placebo-treated groups were found in the percentage of patients with AD who developed asthma (10.7%) or other allergic conditions (allergic rhinitis, 22.4%; food allergy, 15.9%; allergic conjunctivitis, 14.1%; one or more atopic comorbidities, 37.0%) by study end. Allergic rhinitis, food allergy, and having one or more atopic comorbidities (but not asthma or allergic conjunctivitis alone) developed significantly more often in infants with greater AD severity at baseline. Pimecrolimus was significantly more effective than vehicle for AD treatment at week 14. Adverse event incidences were similar.. This longitudinal observation of infants with AD provides evidence of the atopic march. Pimecrolimus was safe and effective in infants with mild to moderate AD.

Topics: Asthma; Comorbidity; Dermatitis, Atopic; Dermatologic Agents; Double-Blind Method; Humans; Infant; Longitudinal Studies; Rhinitis, Allergic; Severity of Illness Index; Tacrolimus; Treatment Outcome

In patients with aspirin-exacerbated respiratory disease (AERD), pretreatment with asthma controller medications (leukotriene modifiers, inhaled or systemic corticosteroids, and salmeterol) partially modifies the severity of aspirin-induced asthmatic reactions.. A recent study showed that pretreatment with tacrolimus completely prevented aspirin-induced respiratory reactions and might allow silent aspirin desensitization.. Ten patients with rhinosinusitis, nasal polyps, and asthma had a history of asthma attacks after ingesting aspirin and nonsteroidal anti-inflammatory drugs. All underwent baseline oral aspirin challenges and had typical respiratory reactions. They were then randomized to receive tacrolimus (0.1 mg/kg weight; 8 patients) or placebo (2 patients) in a double-blind protocol before rechallenge with aspirin using the previous provoking dose of aspirin. In addition, respiratory reactions sustained by 50 consecutive patients with AERD during 2004 were recorded, analyzed, and compared with the tacrolimus/placebo-treated patients to determine whether there were any differences.. Tacrolimus pretreatment failed to block respiratory reactions to provoking doses of aspirin in 5 of 8 patients with AERD, and in the other 3 patients did not block higher doses of aspirin. The results of oral aspirin challenges in the control population of 50 patients were compared with either the baseline or postchallenge data from the tacrolimus-pretreated or placebo-pretreated patients with AERD, and there were no significant differences.. Use of tacrolimus as add-on pretreatment to prevent reactions to aspirin in patients with AERD or to achieve the goal of silent aspirin desensitization could not be accomplished.

Topics: Administration, Oral; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Asthma; Desensitization, Immunologic; Double-Blind Method; Drug Hypersensitivity; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Tacrolimus

The exact mechanism of aspirin-induced asthma is not clear. It has been postulated that precipitation of asthma attacks by aspirin is linked to inhibition of COX activity and massive release of cysteinyl leukotriene into the airway. Tacrolimus, a macrolide-derived immunosuppressant, is used for immunosuppression in organ transplantation and also for allergic diseases such as atopic dermatitis.. We evaluated the effects of tacrolimus in aspirin-induced asthma by using a double-blind, crossover study design.. Twelve patients with aspirin-induced asthma (male:female, 3:9; mean age +/- SD, 36.7 +/- 7.2 years) received either tacrolimus (0.1 mg/kg) or placebo 2 hours before the threshold dose of oral aspirin.. In the placebo arm, oral aspirin significantly decreased FEV 1 concomitant with significant increases in sputum eosinophilic cationic protein and urinary leukotriene E(4) levels. Tacrolimus significantly inhibited bronchoconstriction and abrogated aspirin-induced increase in both sputum eosinophilic cationic protein and urinary leukotriene E(4) levels.. The current study suggested that tacrolimus inhibited bronchoconstriction to a threshold dose of aspirin by inhibition of cysteinyl leukotriene excretion.

Topics: Adult; Aspirin; Asthma; ATP Binding Cassette Transporter, Subfamily B; Bronchoconstriction; Cross-Over Studies; Double-Blind Method; Eosinophil Cationic Protein; Female; Humans; Immunosuppressive Agents; Leukotriene E4; Male; Middle Aged; Tacrolimus

Asthma poses a significant threat to public health, with an estimated burden of over 334 million people worldwide. Available treatments are often inadequate. We developed a thermo-sensitive hydrogel vaccine containing allergen and FK506 that induced immune tolerance via intranasal administration to treat experimental allergic asthma. The hydrogel delivery system was formulated based on Poloxamer 407 (P407), Carbopol 974P NF, and Polyoxyl 15 hydroxystearate (Kolliphor HS15, HS15). It flowed freely at room temperature and rapidly formed a hydrogel in the nasal cavity once the temperature rose over 33 °C. Ovalbumin and FK506 were slowly released from the hydrogel form and their mucosal residence time was significantly prolonged compared to the liquid formulation. In both an OVA-induced asthma model and an HDM-induced asthma model, the vaccines formulated in hydrogel gave lower levels of eosinophilic inflammation, and airway remodeling. The reduction of lung function was ameliorated, and Foxp3-expressing CD4 + Treg cells were significantly higher. The frequency of Foxp3 + Tregs in lung-draining lymph nodes (dLNs) was correlated with the amelioration. Depletion of Foxp3 + Treg cells abolished the beneficial effects of the allergen/FK506 hydrogel vaccinations. Thus, the allergen/FK506 hydrogel formulation has the potential to be a delivery system for therapeutic allergy vaccines to induce immune tolerance.

Topics: Allergens; Asthma; Disease Models, Animal; Forkhead Transcription Factors; Humans; Hydrogels; Immunotherapy; Ovalbumin; T-Lymphocytes, Regulatory; Tacrolimus; Vaccines

Eosinophils are a common clinical feature associated with chronic allergic diseases, and elemental diets, systemic steroids, anti-IL-5 and anti-IL-13 treatment have shown some therapeutic promise. Herein, we present evidence that pre- and post-intraperitoneal administration of tacrolimus (FK506) is very effective in reducing CCR3/Siglec-F

Topics: Allergens; Animals; Apoptosis; Aspergillosis; Aspergillus; Asthma; Calcium-Binding Proteins; Enteritis; Eosinophilia; Eosinophils; Fibrosis; Gastritis; Humans; Hypersensitivity; Immunosuppressive Agents; Interleukin-13; Interleukin-5; Lung; Mice; Mice, Inbred BALB C; Mice, Transgenic; Muscle Proteins; Respiratory Mucosa; Tacrolimus

In this paper, we aimed to explore the potential mechanism underlying atopic dermatitis (AD) and its association with asthma. The BALB/c mice were randomly assigned to three groups, including the vehicle control (VD) group, the AD group, and the treatment (TR) group. The AD mice model was successfully constructed in the AD and TR group. The dermatitis severity scores and skin lesions were significantly increased in AD mice after DNCB application. Airway responsiveness in the AD group was significantly higher than in the TR group. The number of inflammatory cells was increased in skin lesions and bronchoalveolar lavage fluid (BALF) of AD mice. The levels of IL-4, IL-5, IFN-γ, and OVA-IgE in BALF supernatants of mice in the AD group were higher than those in the VC group. All the changes in AD mice were decreased by tacrolimus. These results indicate that AD may be a significant risk factor for atopic asthma development.

Topics: Animals; Asthma; Bronchoalveolar Lavage Fluid; Dermatitis, Atopic; Dinitrochlorobenzene; Eczema; Mice; Mice, Inbred BALB C; Tacrolimus

Clinicians and patients continue to convey interest in personalized medicine. The objective of personalized medicine is to improve healthcare by tailoring disease prevention, diagnosis, and treatment strategies for individuals based on their unique clinical history and genetic composition. This article offers an overview of pharmacogenomics, discusses caveats specific to pharmacogenomics in pediatric populations, provides evidence-based recommendations for pediatric clinicians, and offers insight regarding the future role of pharmacogenomics testing in pediatric medicine. Reviews of the current literature and thoughtful discussions are presented regarding the pharmacogenomics of antidepressants, codeine and oncologic, asthma, and immunomodulatory pharmacotherapies.

Topics: Antidepressive Agents; Asthma; Child; Codeine; Cytochrome P-450 CYP2D6; Humans; Immunologic Factors; Mercaptopurine; Methotrexate; Pediatrics; Pharmacogenetics; Polymorphism, Single Nucleotide; Tacrolimus

To explore the efficacy of intranasal treatment by immunosuppressant tacrolimus for allergic asthma and its mechanism in mice.. 24 female BALB/c mice were randomly divided into 4 groups: group A (negative control), group B (model control), group C (low dose treatment), and group D (high dose treatment). Mice in group A were treated with saline (100 microl). Other groups were sensitized intraperitoneally with allergen extracts of Dermatophagoides farinae (Der f) absorbed to Al(OH)3 at day 0, 7, and 14. From day 28, groups A, B, C, and D were intranasally treated with saline, PBS, 0.01% tacrolimus, and 0.1% tacrolimus, respectively, once per day for 7 d, and followed by intranasal challenge with 50 microl Der f extracts in the mean time. 24 h after the last challenge, the airway hyper-responsiveness (AHR) were detected. At 48 h after the last challenge, the mice were sacrificed, the bronchoalveolar lavage fluid (BALF) was collected, the lungs and spleen were aseptically removed. The total cell number and cell classification of BALF were recorded. The level of interleukin-4 (IL-4), interleukin-5 (IL-5), interferon-gamma (IFN-gamma) in BALF and in spleen cells culture supernatants was detected by ELISA. The lung inflammation and mucus secretion were observed in mice by HE (haematoxylin and eosin) staining and AB (Alcian Blue) staining.. Compared with group B, AHR (P < 0.05) and airway inflammation in group D significantly reduced. The number of total cells [(29.92 +/- 5.20) x 10(4)/ml] (P < 0.05) and eosinophils [(4.33 +/- 0.75) x 10(4)/ml] (P < 0.01) in group D greatly decreased than those of group B [(59.33 +/- 5.99) x 10(4)/ml and (22.67 +/- 5.65) x 10(4)/ml]. The level of IL-4 [(22.49 +/- 4.96) pg/ml] (P < 0.05), IL-5 [(43.90 +/- 13.15) pg/ml] (P < 0.01) and IFN-gamma [(10.17 +/- 1.09) pg/ml] (P < 0.05) in BALF significantly decreased (P < 0.05) than those of group B [(57.02 +/- 7.38), (133.49 +/- 15.63) and (15.32 +/- 3.23) pg/ml, respectively]. The level of IL-4 [(22.54 +/- 4.58) pg/ml], IL-5 [(3631 +/- 20.85) pg/ml] and IFN-gamma [(11.28 +/- 1.79) pg/ml] in spleen cell culture supernatant all significantly decreased (P < 0.05) than those of group B [(56.34 +/- 6.21), (72.3 +/- 6.23) and (18.82 +/- 1.88) pg/ml, respectively]. There was no significant difference between group C and group B.. Tacrolimus shows certain immune therapeutic effect on dust mite sensitized mice, and this effect may be attributed to its inhibition on T lymphocyte factor secretion.

Topics: Administration, Intranasal; Allergens; Animals; Antigens, Dermatophagoides; Asthma; Bronchoalveolar Lavage Fluid; Female; Immunosuppressive Agents; Inflammation; Interferon-gamma; Interleukin-4; Interleukin-5; Mice; Mice, Inbred BALB C; Tacrolimus

Churg-Strauss syndrome (CSS), which is characterized by systemic small-vessel vasculitis of unknown etiology, is associated with a history of asthma. Although reports of CSS occurring in children are limited, effective treatment of pediatric patients with severe CSS remains challenging. A 10-year-old Japanese boy with a 6-month history of asthma treated with a leukotriene modifier, pranlukast, developed high fever, pleural infiltration, and pericarditis that were associated with marked hypereosinophilia (10,350 eosinophils/µl). Owing to his persistent high fever, mononeuritis multiplex, and severe abdominal pain that was refractory to prednisolone, his general condition progressively deteriorated thereafter. Although intravenous high-dose immunoglobulin administration was transiently effective for mononeuritis multiplex, the recurrent high fever and severe abdominal pain remained refractory. An endoscopic study revealed ulcerative lesions of the total colon. In this context, we treated the patient with an aggressive multidrug immunosuppressive regimen consisting of a high-dose methylprednisolone pulse plus short-course intravenous cyclophosphamide pulse therapy, followed by oral tacrolimus combined with prednisolone. After the rescue multidrug treatment, his severe clinical signs dramatically subsided within a short time, and the concomitantly administered prednisolone was successfully tapered without flare. At present, 12 months after the presentation, he is free from CSS signs or therapy-related toxicity except for an occasional mild asthma attack. Although further close observation should be needed to draw a long-term outcome in this patient, we believe that aggressive multidrug immunosuppressive treatment should be considered as an alternative rescue treatment in selected patients with severe CSS, even with pediatric-onset disease, that is refractory to prednisolone.

Topics: Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Child; Chromones; Churg-Strauss Syndrome; Cyclophosphamide; Drug Resistance; Drug Resistance, Multiple; Eosinophilia; Humans; Immunosuppressive Agents; Japan; Methylprednisolone; Pericarditis; Pleura; Prednisolone; Tacrolimus; Ulcer

Topics: Aged; Asthma; Blood Vessels; Churg-Strauss Syndrome; Comorbidity; Eosinophilia; Female; Humans; Immunosuppressive Agents; Myasthenia Gravis; Osteoporosis; Prednisolone; Skin; Tacrolimus; Treatment Outcome

To examine the 10-year outcome of affected body surface area (BSA), respiratory symptoms, and serum IgE in adult AD patients 6 years after a 4-year intervention with topical tacrolimus.. Patients who 10 years ago participated in a 4-year, open tacrolimus study (n = 65) were contacted for assessment of affected BSA, bronchial hyper-reactivity (BHR), respiratory symptoms, skin prick tests and serum IgE.. Altogether, 50 (77%) patients attended the follow-up visit. The median affected BSA decreased from 19% to 1.6% during the 10-year follow-up (p < 0.0001). Patients with active asthma and rhinitis symptoms at baseline reported a significant decrease at the follow-up (p = 0.02 andp = 0.01). In patients with BHR at baseline, the provocative dose of inhaled histamine producing a 15% decrease in FEV(1) increased. Responders (>or= 60% improvement of affected BSA) to tacrolimus treatment at the 1-year visit had a significantly smaller affected BSA at the 4- and 10-year visits than non-responders (< 60% improvement). Responders also showed a significant decrease in serum IgE at the follow-up visit compared to baseline (p = 0.002).. The long-term, effective treatment of patients with AD may have a beneficial effect on affected BSA, respiratory symptoms, and serum IgE.

Topics: Administration, Topical; Adolescent; Adult; Asthma; Body Surface Area; Bronchial Hyperreactivity; Cohort Studies; Dermatitis, Atopic; Dose-Response Relationship, Drug; Drug Administration Schedule; Eczema; Female; Follow-Up Studies; Humans; Immunoglobulin E; Male; Middle Aged; Respiratory Function Tests; Retrospective Studies; Risk Assessment; Skin Tests; Tacrolimus; Time Factors; Young Adult

Topics: Administration, Topical; Adolescent; Adult; Animals; Asthma; Bronchial Hyperreactivity; Dermatitis, Atopic; Follow-Up Studies; Humans; Immunosuppressive Agents; Middle Aged; Prospective Studies; Tacrolimus

One of the characteristic features of asthma is a persistent pulmonary inflammation, with increased numbers of eosinophils and activated T-lymphocytes in the airways. T-helper cells of the Th2 phenotype play a pivotal role in the pathogenesis of asthma, and they are believed to orchestrate the asthmatic response by releasing a wide repertoire of cytokines. Herein, we describe the design, synthesis, and evaluation in models of allergic asthma of a locally active T-cell modulator, MLD987 (1). Compound 1 is a potent immunosuppressant that inhibits the activation, proliferation, and release of cytokines from T-cells with IC(50) values in the low nanomolar range. In a Brown-Norway rat model of allergic asthma, 1, when given into the airways by intratracheal administration (ED(50) = 1 mg/kg) or by inhalation (ED(50) = 0.4 mg/kg), potently reduced the influx of leukocytes into bronchoalveolar lavage fluid samples obtained from antigen-challenged animals. In contrast, 1 had an appreciably weaker activity in this model when given orally or intravenously. Pharmacokinetic evaluation in rat and rhesus monkey showed that 1 had both a low oral (2-4%) and a low pulmonary (7%, monkey) bioavailability. These findings are consistent with a local site of action of the compound and rule out that its antiinflammatory activity in the lung was caused by systemically absorbed material, which had been swallowed during inhalation or which had entered the circulation via the airways. Local administration and the metabolically soft structure of 1, which favors rapid systemic metabolism to less immunosuppressive metabolite 2, are the main reasons for the low exposure and weak systemic activity of the compound. Administration of a locally active compound such as 1, by inhalation, should reduce systemic side effects. Our results indicate that 1 has the potential to serve as an alternative to inhaled glucocorticosteroids for the long-term therapy of asthma of all grades of severity.

Topics: Administration, Inhalation; Animals; Anti-Inflammatory Agents; Area Under Curve; Asthma; Biochemistry; Cells, Cultured; Drug Design; Eosinophils; Half-Life; Humans; Macaca mulatta; Macrolides; Rats; Rats, Inbred BN; Structure-Activity Relationship; T-Lymphocytes; Tacrolimus

The cysteinyl leukotriene receptor 1 (cysLTR1) antagonists are useful for oral treatment of bronchial asthma. The underlying mechanism of cysLTR1 antagonists on inhibition of inflammatory cytokine production is yet to be determined.. The present study was designed to determine the effect of pranlukast, a cysLTR1 antagonist, on production of inflammatory cytokines by allergen-stimulated peripheral blood monocytes (PBM) from atopic asthmatics.. PBM were obtained from normal control (n = 10) and Dermatophagoides farinae (Der f) allergen-sensitized atopic asthmatics (n = 12), and were cultured in the presence of Der f allergen. The production of TNF-alpha and nuclear-translocation of nuclear factor kappa B (NF-kappa B) was determined. In atopic asthmatics, pranlukast, tacrolimus or dexamethasone was added before stimulation by Der f. The additive effect of pranlukast and dexamethasone was also determined.. PBM from atopic asthmatics cultured with Der f exhibited a significant increase in TNF-alpha production and nuclear translocation of NF-kappa B compared with normal control (P < 0.01). Pranlukast, tacrolimus and dexamethasone significantly inhibited production of TNF-alpha and nuclear-translocation of NF-kappa B in PBM of atopic asthmatics (P < 0.01). An additive effect of pranlukast on low-dose dexamethasone was also demonstrated. However, LTD4 did not induce TNF-alpha production or NF-kappa B nuclear translocation.. Our results suggest that pranlukast may inhibit TNF-alpha production via suppression of NF-kappa B activation through pathways distinct from cysLTR1 antagonism.

Topics: Adult; Allergens; Antigens, Dermatophagoides; Arthropod Proteins; Asthma; Cells, Cultured; Chromones; Cysteine Endopeptidases; Cytokines; Dermatophagoides farinae; Dexamethasone; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Leukocytes, Mononuclear; Leukotriene Antagonists; Male; NF-kappa B; Tacrolimus; Translocation, Genetic; Tumor Necrosis Factor-alpha

Immunomodulators include both immunostimulatory and immunosuppressive agents. Obligate contact sensitizers such as diphencyprone or dinitrochlorobenzene have been used against viral and autoimmune diseases. Newer agents such as the toll-like receptor agonists imiquimod and resiquimod have been clinically used to treat viral infections and skin cancers in immunocompetent and immunosuppressed patients. On the other hand, the topical immunosuppressive agents tacrolimus and pimecrolimus have been used with great success in the treatment of chronic inflammatory diseases in children and adults. The introduction of this new class of drugs (i.e. Calcineurin inhibitors) marked the beginning of the post-cortisone era in clinical dermatology. Toll-like receptor agonists and calcineurin antagonists will supplement corticosteroids to improve specific dermatological therapy. Topical immunotherapy with both immunostimulatory and immunosuppressive agents show potential for effective and patient-friendly treatment of inflammatory, infectious and neoplastic skin diseases. Long-term evaluation will define the tolerability and the safety profile.

Topics: Adjuvants, Immunologic; Administration, Topical; Adult; Aged; Aged, 80 and over; Aminoquinolines; Asthma; Autoimmune Diseases; Bowen's Disease; Child; Cyclopropanes; Dermatitis, Atopic; Dinitrochlorobenzene; Female; Follow-Up Studies; Herpes Simplex; Humans; Imidazoles; Imiquimod; Immunity, Cellular; Immunocompromised Host; Immunoglobulin A; Immunosuppressive Agents; Lichen Sclerosus et Atrophicus; Male; Molluscum Contagiosum; Papillomavirus Infections; Precancerous Conditions; Skin Diseases; Skin Diseases, Viral; Skin Neoplasms; Tacrolimus; Time Factors; Warts

Cyclosporine A (CsA) and tacrolimus (Tac), both calcineurin inhibitors, have been used extensively for immunosuppressive therapy in pediatric liver transplant recipients. They share a similar mechanism of action, the inhibition of cytokine gene transcription primarily interleukin-2 (IL-2) in T lymphocytes. Despite the strong immunosuppressive property, there are several reports of food allergy in pediatric transplant recipients under Tac immunosuppression, but not CsA. In this paper we report on 3 of 50 pediatric liver transplant recipients diagnosed with food allergy and asthma while receiving systemic Tac/CsA immunosuppression and the discuss the role of calcineurin inhibitors in this situation.

Topics: Adolescent; Asthma; Child; Child, Preschool; Cyclosporine; Drug Therapy, Combination; Food Hypersensitivity; Humans; Immunosuppressive Agents; Liver Transplantation; Retrospective Studies; Tacrolimus

1. IL-13 is an important mediator in inflammatory diseases such as asthma. IL-13 is mainly produced by T cells. However, signalling pathways leading to induction of this cytokine are not well-characterized. We analysed the regulation of IL-13 in human peripheral blood mononuclear cells and CD4(+) T cells. 2. Cyclosporine (CsA) and FK-506 inhibited IL-13 synthesis, when cells were stimulated by TPA/ionomycin. However, stimulation by alpha-CD3/alpha-CD28 led to an enhanced IL-13 synthesis. 3. NF-kappa B inhibitor N-tosyl-L-lysine chloromethylketone (TLCK) inhibited IL-13 synthesis more effectively after TPA/ionomycin stimulation. After alpha-CD3/alpha-CD28 stimulation, only 300 microM TLCK inhibited IL-13 synthesis. Dexamethasone inhibited IL-13 equally effective after alpha-CD3/alpha-CD28 and TPA/ionomycin stimulation. 4. p38 MAPK inhibitor SB203580 inhibited IL-13 synthesis only partially. MEK inhibitor U0126 inhibited TPA/ionomycin induced IL-13 synthesis very effectively, whereas alpha-CD3/alpha-CD28 stimulated IL-13 induction was resistant to this drug. 5. These results were confirmed in purified CD4(+) T cells. In difference to PBMCs alpha-CD3/alpha-CD28 stimulated IL-13 synthesis was effectively inhibited by CsA, FK-506 and U0126. 6. Therefore U0126 was tested in an animal model of allergic asthma. We could demonstrate for the first time that inhibition of the MEK - ERK cascade is a therapeutic option for asthma. Intraperitoneal administration of 10 mg kg(-1) U0126 reduced lung eosinophilia in ovalbumin-challenged Brown Norway rats by 44%. 7. These results demonstrate that different signalling pathways are involved in regulating IL-13 synthesis in primary human T cells. Characterizing highly potent inhibitors of IL-13 synthesis can be exploited to identify new drugs to treat immunological diseases such as asthma.

Topics: Animals; Anti-Asthmatic Agents; Asthma; Butadienes; Calcium Signaling; CD4-Positive T-Lymphocytes; Cells, Cultured; Cyclosporine; Disease Models, Animal; DNA-Binding Proteins; Enzyme Inhibitors; Humans; Inhibitory Concentration 50; Injections, Intraperitoneal; Interleukin-13; Leukocytes, Mononuclear; Lymphocytes; Male; MAP Kinase Signaling System; Mitogen-Activated Protein Kinases; NF-kappa B; NFATC Transcription Factors; Nitriles; Nuclear Proteins; Pulmonary Eosinophilia; Rats; Rats, Inbred BN; RNA, Messenger; Tacrolimus; Time Factors; Transcription Factors

Helper T cells are involved in the pathophysiologic condition of asthma, so modulation of cytokine production may be effective therapy.. We aimed to selectively control the synthesis of IL-5 by helper T cells and tested in vivo effects using a murine asthma model.. The effect of dexamethasone, FK506, cyclosporin A, and nonactin (a macrolide compound produced by Streptomyces griseus) on cytokine production by allergen-specific T-cell clones was determined. The effect of these agents and an anti-IL-5 neutralizing antibody on airway eosinophilic inflammation was investigated in a murine asthma model.. Dexamethasone, FK506, and cyclosporin A suppressed the production of IL-2, IL-4, and IL-5 by human helper T cells, which shows a similar concentration-response relationship in each case. Cyclosporin A and dexamethasone inhibited airway eosinophilia in vivo. Nonactin suppressed IL-5 synthesis but not IL-2 or IL-4 synthesis, and it also significantly suppressed airway eosinophilia.. Nonactin only suppressed IL-5 synthesis and was as effective against eosinophilia as cyclosporin A and dexa-methasone, which indicates that IL-5 is a reasonable therapeutic target in allergic disorders that are accompanied by eosinophilic inflammation.

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Asthma; Clone Cells; Cyclosporine; Dexamethasone; Disease Models, Animal; Dose-Response Relationship, Drug; Eosinophilia; Humans; Immunosuppressive Agents; Inflammation; Interleukin-2; Interleukin-4; Interleukin-5; Macrolides; Mice; Mice, Inbred BALB C; T-Lymphocytes; T-Lymphocytes, Helper-Inducer; Tacrolimus

A series of 32-(O)-acylated and 32-(O)-thioacylated derivatives of the antibiotic ascomycin (1) have been synthesized. These readily accessible analogues exhibit potent immunosuppressive activity in vitro, as measured by an interleukin-2 reporter gene assay and the mixed lymphocyte reaction. Such molecules are expected to have a therapeutic potential in chronic inflammatory diseases of the airways such as asthma.

Topics: Acylation; Anti-Bacterial Agents; Asthma; Immunosuppressive Agents; Inhibitory Concentration 50; Tacrolimus

Topics: Anti-Bacterial Agents; Asthma; Clarithromycin; Eosinophils; Erythromycin; Fosfomycin; Humans; Hypersensitivity; Immunosuppressive Agents; In Vitro Techniques; Interleukin-8; Josamycin; Tacrolimus

A number of structurally different allergens trigger the release of mediators from basophils by cross-linking of IgE receptors. In this study, we analyzed the effects of cyclosporine A (CSA) and FK-506 on allergen-induced histamine release in human blood basophils obtained from birch- or grass-pollen-allergic donors (n = 12). Preincubation of basophils with CSA (0.003-3 microg/ml) or FK-506 (0.003-3 microg/ml) led to inhibition of histamine release induced by purified recombinant tree pollen allergens (r Bet v 1, r Bet v 2) and timothy grass pollen allergens (r Ph1 p 1, r Ph1 p 2, r Ph1 p 5). The effects of CSA and FK-506 were dose dependent, with IC50 values ranging between 0.03 and 0.3 microg/ml for both CSA and FK-506. Cyclosporine H, an inactive CSA analog, did not show any effect on allergen-induced histamine secretion. IgE dependency of the reaction was demonstrated in passive transfer experiments using highly enriched human basophils (> 95% pure) and specific IgE from a patient allergic to Bet v 2. In summary, our data show that CSA and FK-506 inhibit recombinant-allergen-induced histamine release from peripheral blood basophils in allergic donors.

Topics: Adult; Allergens; Asthma; Basophils; Conjunctivitis, Allergic; Cyclosporine; Female; Histamine Release; Humans; Immunization, Passive; Immunoglobulin E; Immunosuppressive Agents; In Vitro Techniques; Male; Middle Aged; Pollen; Rhinitis, Allergic, Seasonal; Tacrolimus

We have previously shown that T-lymphocytes from clinically glucocorticoid (GC) resistant asthmatics are more refractory to dexamethasone suppression in vitro than those of GC sensitive asthmatics. We wished to extend these observations to compare three GCs used topically for asthma therapy (budesonide, beclomethasone dipropionate and fluticasone 17 alpha-propionate) and three immunosuppressive drugs (cyclosporin A, FK506 (tacrolimus) and mycophenolate mofetil) with dexamethasone for their antiproliferative effects on T-lymphocytes from GC sensitive and resistant asthmatics, and also to compare the rates of steroid metabolism by T-lymphocytes from these patients. Antiproliferative activity of the drugs was measured on peripheral blood T-lymphocytes activated with phytohaemagglutinin (PHA) and anti-CD3 antibody in vitro. The rates of total steroid metabolism and 20 alpha-hydroxylation by T-cell homogenates were measured using radiolabelled progesterone as an established probe substrate. Over a wide concentration range, T-lymphocytes from GC resistant asthmatics were significantly less inhibited by all four GCs as compared with cells from GC sensitive asthmatics. The median inhibitory concentrations (IC50) for inhibition of T-lymphocytes from the GC resistant asthmatics exceeded those likely to be achieved therapeutically by systemic administration (although higher concentrations might in theory be achieved locally in the bronchial mucosa by inhaled administration). In contrast, all three immunosuppressive drugs at putative therapeutic concentrations inhibited T-lymphocytes both from GC sensitive and resistant asthmatics with equivalent potency. The rates of total metabolism and 20 alpha-hydroxylation of steroid by homogenates of T-lymphocytes from GC sensitive and resistant asthmatics were equivalent. Thus, relative GC resistance in T-lymphocytes from GC resistant as compared with sensitive asthmatics is: 1) manifest with GC molecules of variable molecular structure; 2) not accompanied by elevated intracellular metabolism of steroids; and 3) overcome by immunosuppressive drugs which inhibit T-lymphocytes by non-GC-mediated mechanisms. We conclude that current anti-asthma glucocorticoids at therapeutic concentrations are unlikely to be of benefit for the therapy of glucocorticoid resistant asthma, and that other immunosuppressive drugs may have potential as therapeutic agents in these patients.

Topics: Administration, Topical; Adult; Aged; Androstadienes; Anti-Inflammatory Agents; Asthma; Beclomethasone; Budesonide; CD3 Complex; Cell Division; Cyclosporine; Dexamethasone; Drug Resistance; Female; Fluticasone; Glucocorticoids; Humans; Hydroxylation; Immunosuppressive Agents; Lymphocyte Activation; Male; Middle Aged; Molecular Structure; Mycophenolic Acid; Phytohemagglutinins; Pregnenediones; T-Lymphocytes; Tacrolimus

In order to investigate the role of IL-5 in allergic airway inflammation and hyperresponsiveness, the effects of rat anti-IL-5 monoclonal antibody (NC-17), recombinant soluble murine IL-5 receptor, and some immunosuppressors were studied in mice model. Three inhalations of an antigen by actively sensitized animals resulted in an increase in airway reactivity to acetylcholine. Twenty-four hours after the final inhalation, the number of leukocytes (mononuclear cells and eosinophils) and the amount of IL-4 and IL-5 in bronchoalveolar lavage fluid (BALF) increased significantly. NC-17 and soluble IL-5 receptor inhibited the antigen-induced increase of eosinophils with little effect on bronchial hyperreactivity. Cyclosporin A, FK-506, and cyclophosphamide clearly inhibited the antigen-induced increase of IL-5 and eosinophils in BALF. Airway hyperreactivity is inhibited by cyclosporine A and FK-506 but not by cyclophosphamide. Furthermore, to investigate the role of mast cells in the onset of allergic airway hyperreactivity, we have examined the effect of repeated antigen provocation in WBB6F1-W/Wv mice (W/Wv), mast-cell-deficient mice. Whereas significant elevation of IL-5 level and the number of eosinophils on BALF was observed, airway reactivity to acetylcholine was not changed at all. These results indicate that IL-5 may play an important role for the antigen-induced eosinophilia in BALF but not in airway hyperresponsiveness in mice.

Topics: Acetylcholine; Animals; Asthma; Bronchial Hyperreactivity; Cyclophosphamide; Interleukin-4; Interleukin-5; Male; Mice; Mice, Inbred BALB C; Mice, Nude; O Antigens; Rats; Tacrolimus

IL-5 was produced in vitro by peripheral blood mononuclear cells (PBMC) of mite-sensitive atopic patients upon challenge with specific allergen, while PBMC of healthy controls produced essentially no IL-5. Stimuli delivered by the combination of phorbol ester and Ca2+ ionophore induced marked IL-5 production by PBMC obtained from atopic and non-atopic asthmatics, suggesting that both protein kinase C and Ca2+ influx are required for IL-5 production. CD2- or CD4-bearing cell depletion almost completely removed IL-5-producing cells while CD8-bearing cell depletion rather enriched them. These findings indicate that CD4+ T cells are the principal source of IL-5 in PBMC. The capacity of PBMC of atopic asthmatics, non-atopic asthmatics and healthy controls to produce IL-2, IL-4, IL-5 and IFN-gamma was compared, to find that cytokine-producing capacities other than that of IL-5 (IL-2, IL-4 and IFN-gamma) were not significantly different among the three groups. Dexamethasone, FK506 and cyclosporin A suppressed IL-5 production in vitro in a dose-dependent manner. Clear dose-dependent suppression of IL-5 gene expression by FK506 was also observed. Treatment of asthmatic patients with inhaled glucocorticoid (beclomethasone dipropionate) ameliorated clinical symptoms, improved lung function and markedly suppressed IL-5 production by PBMC, suggesting the essential role of IL-5 in the pathogenesis of bronchial asthma and the clinical importance of its regulation.

Topics: Adult; Animals; Antigens, Dermatophagoides; Asthma; Base Sequence; Beclomethasone; Calcium; CD4-Positive T-Lymphocytes; Cells, Cultured; Cyclosporine; Dexamethasone; Dose-Response Relationship, Drug; Glucocorticoids; Glycoproteins; Humans; Hypersensitivity, Immediate; Interferon-gamma; Interleukin-2; Interleukin-4; Interleukin-5; Ionomycin; Lymphocyte Activation; Mites; Molecular Sequence Data; Protein Kinase C; Signal Transduction; Tacrolimus; Tetradecanoylphorbol Acetate

Bronchial asthma is associated with eosinophilic inflammation and expression of T-cell-derived cytokines, which influence eosinophilic function. FK506, a newly established immunosuppressive agent, may have potential as a therapeutic instrument for asthma because of its suppressive effect on T-cell activation. To assess this, we compared the inhibitory effects of FK506 and cyclosporin A on production of granulocyte/macrophage colony-stimulating factor and interleukin-5 by interleukin-2- or Dermatophagoides farinae-stimulated mononuclear cells from patients with asthma, and their contribution to proliferation and survival of eosinophils in vitro. FK506 inhibited granulocyte/macrophage colony-stimulating factor production by stimulated mononuclear cells from asthma patients at lower concentrations than cyclosporin A. Both drugs inhibited eosinophil proliferation and survival activity from mononuclear cells at comparable concentrations. Interleukin-5 production by stimulated mononuclear cells was also inhibited both by FK506 and cyclosporin A. We conclude that both FK506 and cyclosporin A have potential for therapy of bronchial asthma.

Topics: Asthma; Cells, Cultured; Cyclosporine; Enzyme-Linked Immunosorbent Assay; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Immunosuppressive Agents; Interleukin-5; Leukocytes, Mononuclear; Tacrolimus

Upon stimulation with phorbol ester and ionomycin, peripheral blood mononuclear cells (PBMC) of atopic patients with moderate eosinophilia produced significantly higher amounts of IL-5 compared to that of normal subjects. This finding renders further support to the notion that T cell-eosinophilic inflammation plays a central role in allergic disorders. IL-5 induction in vitro was completely inhibited by immunosuppressant FK506, cyclosporin A and dexamethasone. FK506 applied in vivo effectively suppressed clinical symptoms of atopic dermatitis and IL-5 production of PBMC. FK506 and cyclosporin A may become a better therapeutic modality against allergic diseases.

Topics: Administration, Topical; Asthma; Calcium; Cyclosporine; Dexamethasone; Humans; Hypersensitivity, Immediate; Interleukin-5; Ionophores; Leukocytes, Mononuclear; Phorbol Esters; Tacrolimus

We examined the eosinophil viability-enhancing activity (EVEA) of peripheral blood mononuclear cells (PBMNCs) obtained from mite-sensitive bronchial asthma (BA) and normal control subjects. Mite concentrations of 1 and 10 micrograms/ml significantly increased EVEA in BA patients as compared with normal controls (p < 0.05 and p < 0.05, respectively). The level of IFN-gamma in PBMNC culture supernatants was higher in BA patients than in normal controls. Dexamethasone, cyclosporin A and FK506 significantly inhibited EVEA in BA patients (p < 0.05 to p < 0.001).

Topics: Allergens; Animals; Antibodies; Asthma; Cell Survival; Cyclosporine; Cytokines; Dexamethasone; Eosinophils; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Interferon-gamma; Interleukin-3; Interleukin-5; Mites; Tacrolimus

Eosinophils are known to play an important role in the pathogenesis of asthma and other allergic diseases. This study demonstrated the effects of various drugs on eosinophil viability in vitro, which might help clinicians and researchers in treating and studying eosinophilic diseases. Staurosporine, a protein kinase C inhibitor, and herbimycin A, a tyrosine kinase inhibitor, at 10(-6) M and 10(-7) M significantly lowered eosinophil viability in a dose-dependent fashion (p < 0.002, p < 0.02 and p < 0.001, p < 0.002, respectively). Both staurosporine and herbimycin A reduced eosinophil survival in a time-dependent fashion at 10(-6) M and 10(-7) M. Ketotifen at 10(-4) M and theophylline at 10(-3) M, significantly decreased eosinophil viability (p < 0.001 and p < 0.001, respectively) in the presence of 100 pg/ml of recombinant human interleukin-5 (rhIL-5). Both FK506 and cyclosporin A at 10(-4) M significantly reduced eosinophil viability (p < 0.001 and p < 0.005, respectively) in the presence of 100 pg/ml of rhIL-5. Our data show that ketotifen, theophylline, FK506, cyclosporin A reduced eosinophil viability at a high concentration. Furthermore, it is suggested that protein kinase C and tyrosine kinase are involved in eosinophil survival.

Topics: Alkaloids; Asthma; Benzoquinones; Cell Survival; Cyclosporine; Eosinophils; Humans; Ketotifen; Lactams, Macrocyclic; Protein Kinase C; Protein-Tyrosine Kinases; Quinones; Rifabutin; Staurosporine; Tacrolimus; Theophylline

We examined the eosinophil viability-enhancing activity (EVEA) of peripheral blood mononuclear cells (PBMNCs) obtained from 6 patients with mite-sensitive bronchial asthma (BA) and 9 normal control subjects. Mite concentrations of 1 microgram/ml and 10 micrograms/ml significantly increased EVEA in PBMNC culture supernatants from BA patients compared with PBMNCs from normal control subjects (76.1 +/- 11.0% at 10 micrograms/ml and 56.3 +/- 16.0% at 1 microgram/ml vs 20.6 +/- 12.6% at 10 micrograms/ml and 7.4 +/- 2.3% at 1 microgram/ml; p < 0.05). The level of IFN-gamma in PBMNC culture supernatants in BA patients was 2.3 +/- 0.9 IU/ml and in normal control subjects 0.7 +/- 0.3 IU/ml. A combination of mAbs (anti-IL-3, anti-IL-5 and anti-GM-CSF, with or without anti-IFN-gamma) neutralized the EVEA (p < 0.001, p < 0.001, respectively). Dexamethasone (10(-8) M to 10(-5) M), cyclosporin A (10(-7) M to 10(-5) M) and FK506 (10(-8) M to 10(-6) M) significantly inhibited EVEA in BA patients (p < 0.05 to p < 0.001). The release of eosinophil cationic protein (ECP) from eosinophils in the presence of mite-stimulated PBMNC culture supernatants was higher in patients with bronchial asthma (569 +/- 147 micrograms/l) than in normal control subjects (203 +/- 99 micrograms/l; p < 0.05).

Topics: Adolescent; Adult; Analysis of Variance; Animals; Asthma; Case-Control Studies; Cell Degranulation; Cell Survival; Cyclosporine; Dexamethasone; Eosinophils; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Interferon-gamma; Interleukin-3; Interleukin-5; Leukocytes, Mononuclear; Middle Aged; Mites; Tacrolimus

We have previously reported that the 5-day culture supernatants of peripheral blood mononuclear cells (PBMC) from Dermatophagides farinae (DF) sensitive asthmatics stimulated with 10 ng/ml DF antigen contain eosinophil chemotactic activity (ECA) with an apparent molecular weight greater than 30000 Da. In the present study, we examined the effects of CyA and FK on the ECA. ECA was tested using modified Boyden chamber method. We found that when CyA or FK was added to the culture throughout the experiment, the production of the factors with ECA by PBMC was inhibited in a dose-dependent manner. These inhibitory effects were unchanged by the addition of a sufficient dose of IL-2 to the culture medium. Isoelectrofocusing of the PBMC culture supernatants consistently yielded a major ECF activity at pH 7.0-7.5. The addition of CyA inhibited this major peak. In conclusion, these results suggest that mononuclear cells stimulated with related antigen produce substances which possess ECA and that CyA and FK can block the production of this substance. Therefore, there is a possibility that an immunosuppressive agent may be useful in bronchial asthma therapy by inhibiting the migration of eosinophils.

Topics: Asthma; Chemotactic Factors, Eosinophil; Cyclosporine; Humans; Leukocytes, Mononuclear; Tacrolimus

We examined the effects of inhaled FK-506, a potent immunosuppressive agent, on increased bronchial responsiveness to acetylcholine and on eosinophil infiltration in a guinea pig models of asthma. The guinea pigs were sensitized by repeated inhalation of ovalbumin (OA). Twenty four hours after antigen challenge, bronchial responsiveness to acetylcholine significantly increased and a marked accumulation of eosinophils in the airways was observed. However, when the guinea pigs were treated with aerosolized FK (10 mg/ml) for 5 min per day for 6 successive days before antigen challenge, the increase in bronchial responsiveness was significantly suppressed and the eosinophil accumulation was strikingly reduced. Since inhaled FK significantly suppressed these responses, there is a possibility that inhaled FK may be a useful therapy for patients with chronic bronchial asthma in the future.

Topics: Acetylcholine; Administration, Inhalation; Animals; Asthma; Bronchial Hyperreactivity; Disease Models, Animal; Eosinophils; Guinea Pigs; Immunity, Cellular; Ovalbumin; Tacrolimus

Using a guinea pig model of asthma, we have shown that the administration of cyclosporin, a T-lymphocyte-selective immunosuppressive agent, from the beginning of the immunization period inhibits the development of the late asthmatic response and bronchial hyperresponsiveness after antigen challenge. Similar results were obtained with FK 506, a new potent immunosuppressive agent. Since these compounds have been shown to suppress the activation of guinea pig T lymphocytes, the present data suggest that T lymphocytes may be important for the elicitation of the late asthmatic response and bronchial hyperresponsiveness.

Topics: Animals; Antigens; Asthma; Bronchi; Bronchial Provocation Tests; Cyclosporins; Guinea Pigs; Male; T-Lymphocytes; Tacrolimus

We examined the effects of FK-506, a potent immunosuppressive agent, on the development of late asthmatic response (LAR) and on the increased bronchial responsiveness to acetylcholine following LAR in guinea pig model of asthma. Guinea pigs sensitized by repeated inhalation of ovalbumin (OA) were intravenously given metopiron 24 hours before and 30 minutes before antigen challenge and to prevent death from immediate severe bronchoconstriction, chlorpheniramine maleate was also injected. When we defined LAR as the responses with a two-fold increase in respiratory resistance during the late phase of antigen challenge, twelve out of fifteen control animals demonstrated apparent LAR. However, when guinea pigs were treated with FK-506 from the beginning of immunization period, the development of LAR was completely inhibited, although similar magnitude of immediate bronchoconstriction was observed, and a subsequent increase in bronchial responsiveness was significantly blocked. We also measured bronchial responsiveness to acetylcholine before, 24 and 72 hours after antigen challenge. FK-506-treated animals inhibited an increase in bronchial responsiveness to acetylcholine. These results suggest that the involvement of cell-mediated immunity may be important in the development of LAR and an increase in bronchial responsiveness.

Topics: Animals; Anti-Bacterial Agents; Asthma; Bronchi; Guinea Pigs; Immunosuppressive Agents; Male; Tacrolimus; Time Factors