Effect of Some Immunosuppressors on Allergic Bronchial Inflammation and Airway Hyperresponsiveness in Mice

Background: The essential role of Th cells and T cell cytokines in eosinophilic inflammation has been established. Methods: To determine whether Th cells are sufficient for the development of airway eosinophilic inflammation, ovalbumin–reactive murine Th clones were established and infused into unprimed mice. Results: Eosinophilic infiltration into the lung was induced upon antigen inhalation in parallel with the rise in bronchoalveolar lavage fluid (BALF) eosinophil peroxidase activity. Neither IgG, IgA, nor IgE antibodies were present in this model. Pathological examination showed swelling and desquamation of epithelial cells, mucous plugs, and goblet cell hyperplasia, all of which well resemble human asthma. Fluorescent probe labeled Th clones migrated into the lung prior to the eosinophil accumulation. Bronchial hyperresponsiveness (BHR) was clearly induced upon antigen inhalation. Anti–IL–5 monoclonal antibody abrogated the responses. Dexamethasone and cyclosporin A suppressed cytokine production by Th cells both in vitro and in vivo, BALF eosinophilia, and BHR. The number of eosinophils recovered in the BALF correlated with the intensity of BHR. Conclusion: The results clearly indicated that monoclonal Th cells are sufficient for the development of both airway eosinophilia and BHR. Agents capable of downregulating IL–5 production seem promising for the treatment of bronchial asthma.

Section: Resultsmentioning

confidence: 99%

Cloned Th Cells Confer Eosinophilic Inflammation and Bronchial Hyperresponsiveness

Kaminuma

Mori²,

Ogawa³

et al. 1999

“…In patients responding to inhaled steroids, IL–5 production by peripheral blood mononuclear cells after therapy is decreased to a larger extent than IL–2 or IL–4 production [51, 88, 89]. Other immunosuppressive compounds, such as FK506 and cyclosporin A, similarly inhibit IL–5 production by suppressing IL–5 gene transcription [90, 91, 92], and have been positioned for the treatment of severe or steroid–resistant bronchial asthma or atopic dermatitis [93, 94]. IL–5 production may also be inhibited via interfering with transcription factors such as nuclear factor (NF) ĸ B or NF IL–5 [95].…”

Section: Il–5 As a Target In Asthma Therapymentioning

confidence: 99%

Role of IL–5 in the Development of Allergen–Induced Airway Hyperresponsiveness

Hamelmann

Gelfand

1999

This review evaluates the role of IL–5 and IL–5–mediated eosinophil airway infiltration in the development of allergen–driven airway hyperresponsiveness. It discusses the structure and function of IL–5 and its receptor and the mechanisms of IL–5–triggered eosinophil accumulation and inflammation of the airways. New research data from murine models of airway inflammation and hyperresponsiveness utilizing different modes of sensitization to allergen and anti–IL–5 antibody or IL–5–deficient knock–out mice underscore the outstanding role of this cytokine in the pathogenesis of bronchial asthma. This review identifies possible directions for future treatment of airway hyperresponsiveness and concludes that targeting IL–5–driven inflammatory responses may be most beneficial for a novel therapy in bronchial asthma.

“…philic inflammation have been demonstrated using various Airway responsiveness was assessed as bronchoconstriction after asthma models [9,10]. These in vivo effects can be ascribed injection of acetylcholine by determining changes in respiratory overto their multiple actions on various cell types determined flow volume as described previously [7].…”

Section: Measurement Of Airway Responsiveness and Bronchoalveolar Lavagementioning

confidence: 99%

IL-5-Producing T Cells that Induce Airway Eosinophilia and Hyperresponsiveness Are Suppressed by Dexamethasone and Cyclosporin A in Mice

Wada

Kaminuma²,

Mori³

et al. 1998

We have recently demonstrated that airway eosinophilic inflammation can be transferred to unprimed mice by infusion of IL-5-producing T cell clones. In this study, we investigated the effects of dexamethasone and cyclosporin A on the airway eosinophilic inflammation in mice transferred with T cell clones. An ovalbumin-reactive T cell clone, KW29, produced IL-5 as well as IL-2 and IL-4 upon stimulation with relevant antigen. Dexamethasone and cyclosporin A dose-dependently suppressed the production of these cytokines in vitro. The number of eosinophils recovered in the bronchoalveolar lavage fluid and the airway responsiveness to acetylcholine were increased in KW29-transferred mice after antigen provocation. Both responses were dose-dependently suppressed by the administration of dexamethasone or cyclosporin A in vivo. We concluded that airway eosinophilic inflammation can be controlled by agents capable of downregulating IL-5 production in T cells.