tacrolimus and Bronchial-Hyperreactivity

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

The participation of mast cells in the induction of antigen-induced airway inflammation and bronchial hyperresponsiveness (BHR) to acetylcholine (ACh) was investigated using pharmacological agents and mast cell-deficient rats (Ws/Ws). A significant increase in the number of leukocytes in bronchoalveolar lavage fluid (BALF) and bronchial responsiveness to ACh were observed 24 h after antigen (ovalbumin) challenge in sensitized Brown-Norway (BN) rats. Disodium cromoglycate and terfenadine did not inhibit antigen-induced airway inflammation and BHR in sensitized BN rats. In contrast, cyclosporin A (CyA), FK-506 and prednisolone significantly inhibited antigen-induced airway inflammation and BHR in sensitized BN rats. In addition, disodium cromoglycate, terfenadine and prednisolone, but not CyA and FK-506, inhibited homologous passive cutaneous anaphylaxis in rats. Furthermore, a significant increase in the number of leukocytes in BALF and BHR was also observed in Ws/Ws rats 24 h after inhalation of antigen; however, the magnitude of BHR in Ws/Ws rats was lower than that in the congenic rats. These findings suggest that mast cells play a partial role in the development of antigen-induced BHR in rats and that the induction of BHR is barely suppressed by mast cell stabilizing agents.

Topics: Acetylcholine; Animals; Anti-Inflammatory Agents; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Cromolyn Sodium; Cyclosporine; Female; Immunosuppressive Agents; Inflammation; Leukocyte Count; Mast Cells; Ovalbumin; Passive Cutaneous Anaphylaxis; Prednisolone; Rats; Rats, Inbred BN; Rats, Wistar; Tacrolimus; Terfenadine

We examined the effect of the immunosuppressive agent, tacrolimus (FK506), on antigen-induced bronchial hyperreactivity to acetylcholine and leukocyte infiltration into the airways of ovalbumin-challenged guinea-pigs. Subcutaneous injection of 0.5 mg/kg of FK506, 1 h before and 5 h after intra-nasal antigen challenge prevented bronchial hyperreactivity to aerosolized acetylcholine, eosinophilia in bronchoalveolar lavage (BAL) fluid and bronchial tissue and the invasion of the bronchial wall by CD4+ T-lymphocytes. FK506 also suppressed ovalbumin-induced increase in the number of leukocytes adhering to the pulmonary vascular endothelium and expressing alpha4-integrins. Inhibition by FK506 of antigen-induced bronchial hyperreactivity in sensitized guinea-pigs may thus relate to its ability to prevent the emergence of important inflammatory components of airway inflammation, such as eosinophil accumulation, as well as CD4+ T-lymphocyte infiltration into the bronchial tissue.

Topics: Acetylcholine; Administration, Intranasal; Animals; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; CD4-Positive T-Lymphocytes; Eosinophils; Guinea Pigs; Immunosuppressive Agents; Inflammation; Injections, Subcutaneous; Male; Ovalbumin; Tacrolimus

1. The effect of the immunosuppressive agent, FK-506, an allergen-induced airways eosinophilia and bronchial hyperreactivity (BHR) in hyper IgE mice (BP2 selection) was investigated. 2. Administration of FK-506 at 2 mg kg-1 s.c., 1 h before and 5 h after the first four ovalbumin challenges, reduced the recruitment of eosinophils into the bronchoalveolar lavage fluid (BALF) from 1.36 +/- 0.22 x 10(5) to 0.53 +/- 0.24 x 10(5) cells ml-1 (n = 5-6, P < 0.05; 60% inhibition), inhibited by 80% BHR in response to i.v. 5-HT and practically suppressed BHR in response to inhaled methacholine. 3. The antigen-induced interleukin (IL)-5 formation in the BALF and serum was inhibited by FK-506 by 75% in both instances. 4. FK-506 failed to modify the bronchoconstriction in BP2 mice, suggesting that different mechanisms are involved in acute bronchoconstriction and BHR. 5. The increased number of CD4+, CD8+, CD3+ T lymphocytes in the BALF to antigen-challenged mice was unaffected by FK-506. 6. These findings indicate that antigen-induced in vivo IL-5 release and eosinophil, but not T-cell, infiltration into the bronchial lumen of sensitized BP2 mice are targets for the anti-allergic activities of FK-506.

Topics: Animals; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Eosinophilia; Fluorescent Antibody Technique, Indirect; Immunoenzyme Techniques; Immunosuppressive Agents; Interleukin-5; Lymphocyte Count; Male; Mice; Mice, Inbred Strains; Ovalbumin; Respiratory Function Tests; 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

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