INTERLEUKIN 12 FUNCTION DURING MURINE LEISHMANIASIS

鼠利什曼病期间白细胞介素 12 的功能

• 批准号: 2057398
• 负责人: FREDERICK P. HEINZEL
• 金额: $ 6.71万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-01 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2057398
• 关键词: B lymphocyte; CD4 molecule; Leishmania major; SCID mouse; T lymphocyte; athymic mouse; cellular immunity; density gradient ultracentrifugation; enzyme linked immunosorbent assay; flow cytometry; gel electrophoresis; immunotherapy; interferon gamma; leishmaniasis; leukocyte activation /transformation; lymphocyte proliferation; macrophage; nucleic acid hybridization; parasitic disease chemotherapy; polymerase chain reaction

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.

小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Th1和Th2 CD4+淋巴细胞亚群的扩增。 这些研究的长期目标是理解基于细胞因子的 产生偏向的CD4+亚群反应的机制。最直接的 目的是描述白介素12的功能和调节。 利什曼病。所请求的工资支持将提供保护 执行所述研究所需的研究时间，以制定 独立的职业生涯，并加强申请人内部的合作 既能提升个人目标又能提升机构目标的机构。CWRU 医学院致力于免疫寄生虫学研究和 为职业发展提供富有成效的支持性环境 这一领域，如独立司的存在所表明的那样 地理医学部和私家侦探的终身教职 跟踪位置。 我们认为IL-12的产生是对感染的严重反应 调节体内的CD4+淋巴细胞反应。IL-12是一种异二聚体 T细胞生长与B细胞产生的干扰素-γ刺激细胞因子 细胞和巨噬细胞。初步研究表明，治疗 重组IL-12对易感BALB/c小鼠完全治愈 感染梅毒过程中Th1免疫功能的变化。此外，生产 在治愈的C57BL/6小鼠中，IL-12的表达显著增加 不愈合的BALB/c小鼠。我们假设IL-12在 感染促进治愈性CD4+Th1应答，而 感染BALB/c和C57BL/6小鼠产生IL-12的原因 他们对利什曼病的不同反应。拟开展的IL-2研究 12在BALB/c和C57BL/6小鼠体内的产生和功能 利什曼病可能为研究利什曼病的寄生性提供独特的机械性见解 感染影响Th1和Th2反应，决定疾病的进程 疾病。 具体目标是： 1)研究IL-12在促进Th1 CD4+亚群选择中的作用 感染利什曼原虫的BALB/c和C57BL/6小鼠的治疗性免疫 少校。 2)确定BALB/c和C57BL/6产生IL-12的差异 利什曼病期间的小鼠。 3)分析IL-12在L专业大鼠体外分化中的作用 -特异性的CD4+T细胞亚群。 4)确定导致B淋巴细胞释放IL-12的刺激因素和 小鼠利什曼病期间的巨噬细胞。