The ultimate goal of this research is to determine how the regulation of cytokine synthesis differs in allergic and non-allergic individuals. Inasmuch as IL-4 is absolutely required for IgE synthesis, and as it upregulates the synthesis of itself and other Th2 cytokines, understanding the mechanisms controlling IL-4 expression is a fundamental problem in allergy. During the previous grant period, we demonstrated that IL-4 synthesis is exaggerated in CD4+ T cells from allergic individuals. Both low antigen concentration and antigen presentation by B cells rather that peripheral blood monocytes preferentially induce IL-4 (Th2) rather than IFN-gamma (TH1) synthesis in T cells. We also showed that the production of IL-12 by macrophages, of I-10 by B cells, and costimulation by CD40 ligand (gp39) are critical parameters regulating cytokine synthesis in T cells. We now propose to: 1. Examine the molecular mechanisms by which B cells enhance IL-4 synthesis in T cells, 2. Determine how antigen presentation by peripheral monocytes enhances IFN-gamma synthesis, and 3. Examine the capacity of alveolar macrophages to present antigen and induce IL-4 synthesis. These studies are based on the hypotheses that antigen presenting cells (APC) control the profile of cytokines produced by CD4+T cells, and that allergic individuals have """"""""defective """""""" APCs which possess either a reduced capacity to produce Il-12 or an increased capacity to produce Il-1-, or both. Our laboratory has generated exciting preliminary results in both murine and human systems regarding the role of APC in the regulation of IL- 4 synthesis. We will focus mainly on antigen specific memory rather than naive T cells, since these are the T cells which produce inappropriate cytokines, are involved in disease pathogenesis and which must be altered in the allergic individual. Moreover, we have assembled a broad range of reagents, that include monoclonal antibodies (anti-CD4OL, -CD28, -IL-10, - IL-12, -B7-1, -B7-2 mAb), cytokines (IL-10 and IL-12), collaborators and a broad range of techniques to fully analyze these problems. The immunological """"""""defect"""""""" that distinguishes atopic from non atopic individuals and allows allergic responses to occur in some but not all individuals, is not yet fully understood. These studies of cytokine regulation in CD4+ T cells will lead to a better understanding of the critical differences in immunologic responses underlying allergy. Such an understanding will be key in the design of novel immunotherapies for allergic disease.
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