INTERLEUKIN 12 FUNCTION DURING MURINE LEISHMANIASIS

鼠利什曼病的治疗和进展是由相互作用介导的 功能不同的Th 1和Th 2 CD 4+淋巴细胞亚群的扩增。 这些研究的长期目标是了解基于精氨酸的 机制负责偏见的CD 4+亚群的反应。 立即 目的是表征IL-12在细胞周期中的功能和调节。 黑热病 所要求的工资支持将提供受保护的 进行所述研究所需的研究时间， 独立的职业生涯，并加强申请人内部的合作 这将促进个人和机构的目标。CWRU 医学院致力于免疫寄生虫学研究， 为职业发展提供富有成效的支持性环境， 这一领域，正如一个独立的司的存在所表明的那样， 地理医学和私家侦探的任务终身职位 跟踪位置。 我们认为，IL-12的产生是对感染的严重反应， 调节体内CD 4+淋巴细胞应答。 IL-12是一种异二聚体 T细胞生长和由B- 细胞和巨噬细胞。 初步研究表明， 易感BALB/c小鼠用重组IL-12恢复完全治愈 Th 1免疫在感染L.少校 并且生产 IL-12的表达在愈合的C57 BL/6小鼠中显著增加， BALB/c小鼠。 我们假设IL-12在 感染促进治愈性CD 4 + Th 1应答， 感染BALB/c和C57 BL/6小鼠产生IL-12解释了 他们对利什曼病的不同反应 IL-1的研究进展 12的产生和功能的BALB/c和C57 BL/6小鼠， 利什曼病可能提供了独特的机械见解， 感染影响Th 1和Th 2反应，决定了 疾病 具体目标是： 1)检查IL-12在促进Th 1 CD 4+亚群选择中的作用， 利什曼原虫感染BALB/c和C57 BL/6小鼠的治疗性免疫 少校 2)确定BALB/c和C57 BL/6产生IL-12的差异 小鼠在利什曼病期间。 3)分析IL-12在L major体外分化中的作用 - 特异性CD 4 + T细胞亚群 4)鉴定导致B淋巴细胞释放IL-12的刺激物， 巨噬细胞在小鼠利什曼病。

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.