Cure and progression of murine leishmaniasis are mediated by reciprocal expansions of functionally distinct Th1 and Th2 CD4+ lymphocyte subsets. The long term goal of these studies is to understand cytokine-based mechanisms responsible for biased CD4+ subset responses. The immediate goals are to characterize the function and regulation of IL-12 during leishmaniasis. The requested salary support will provide protected research time necessary to perform the studies described, to develop an independent career and to strengthen collaborations within the applicant institution that will enhance both personal and institutional goals. CWRU School of Medicine is committed to immunoparasitologic research and provides a productive supportive environment for career development in this field, as indicated by the existence of a free -standing Division of Geographic Medicine and by the assignment of the P.I. to a tenure track position. We propose that IL-12 produced in response to infection critically regulates CD4+ lymphocyte responses in vivo. IL-12 is a heterodimeric T-cell growth and IFN-gamma stimulatory cytokine that is produced by B- cells and macrophages. Preliminary studies show that treatment of susceptible BALB/c mice with recombinant IL-12 restores fully curative Th1 immunity during infection with L. major. Moreover, the production of IL-12 is increased significantly in healing C57BL/6 mice compared to nonhealing BALB/c mice. We hypothesize that IL-12 produced during infection promotes curative CD4+ Th1 responses and that differences in the production of IL-12 by infected BALB/c and C57BL/6 mice account for their disparate responses to leishmaniasis. The proposed studies of IL- 12 production and function in BALB/c and C57BL/6 mice during leishmaniasis may provide unique mechanistic insights into how parasitic infection effects Th1 and Th2 responses that determine the course of disease.
Specific aims are to: 1) Examine the role of IL-12 in promoting Th1 CD4+ subset selection and curative immunity in BALB/c and C57BL/6 mice infected with Leishmania major. 2) Identify differences in the production of IL-12 by BALB/c and C57BL/6 mice during leishmaniasis. 3) Analyze the role of IL-12 in the in vitro differentiation of L major - specific CD4+ T cell subsets. 4) Identify stimuli that result in IL-12 release by B-lymphocytes and macrophages during murine leishmaniasis.
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