Despite advances in our understanding of the pathogenesis of asthma, the morbidity and mortality associated with it are increasing both in the United States and worldwide. Most studies have focused on investigating the pathogenic mechanisms involved in the acute inflammatory aspects of the disease, with little attention given to the mechanisms involved in the long-term chronic processes, which may regulate outcome to recurrent disease or the establishment of tolerance. The focus of this proposal is to investigate the mechanism(s) involved in the establishment of inhalational tolerance in an ovalbumin (OVA)-induced model of allergic airway disease. Our model is unique, in that inhalational tolerance develops subsequent to an intense Th2 response in the lung. We have observed, in lungs, increased levels of the immunoregulatory cytokines transforming growth factor beta (TGFbeta) and IL-10, increased T cells (CD4+ and CD4+/CD25+) and increased B cells with enhanced MHC II expression at both the acute inflammatory stage and chronic tolerant stages in our model. Our overall hypothesis is that TGFbeta synthesizing regulatory T (Tr) cells via antigen presentation by immature B cells induce inhalational tolerance. Specifically, we hypothesize that, as a result of acute allergic inflammation (chemokines and/or cytokines) a resident population of Tr cells expands and becomes activated to inhibit the CD4+ T cell driven inflammatory response. We will investigate this hypothesis with experiments designed to: determine the mechanism(s) of inhalational tolerance; identify the cells responsible for induction of inhalational tolerance; determine if T cells have suppressor activity; and determine if B cells in the lung have antigen presenting characteristics at various stages of the model. The significance of TGFbeta and Tr cells in immune regulation is clearly an evolving exciting field at this time and their possible role in the regulation of allergic airway disease is intriguing. These studies will help elucidate the role and interactions of both Tr cells and B cells in the development of tolerance in this OVA-induced model of allergic airway inflammation.
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