The long-term goal of this research is to understand the mechanisms by which filarial parasites induce differentiation of CD4 cells to produce cytokines indicative of a Th2 response (IL-4, IL-5, IL-10), the dominant Th subset in lymphatic filariasis. Two hypotheses developed on the basis of support data will be tested. First, strong Th2 responses to microfilariae (mf) are induced in vivo by T cell and possibly non-T cell derived cytokines, particularly IL-4. Second, dominance of the Ag-specific Th2 subset is maintained by Th2-derived cytokines that suppress activation of Th1 cells. Based on preliminary data obtained by study of mice sensitized to Brugia malayi mf and infective larvae (L3) antigens, the following specific aims are proposed. 1. Establish the roles of IL-4, IFN-gamma, IL-10, and IL-12 and their cellular sources in determining the bias toward CD4+ Th2 responses to live mf and L3 in vivo. 2. Analysis of in vivo regulation and maintenance of established Th2 responses to mf Ags, with an emphasis on the importance of the balance between IL-10 and IL-12/IFN-gamma. These studies will advance our knowledge of how allergic hypersensitivity reactions to filarial parasites are induced and maintained in vivo.
