INTERLEUKIN-12 AS IMMUNOTHERAPY IN LEISHMANIASIS

这些研究的长期目标是理解基于细胞因子的 治愈性和非治愈性免疫反应的机制 在利什曼病期间。一种具有良好特征的小鼠模型 利什曼病已经为细胞因子提供了重要的见解。 这种疾病的病理学。中国主要乳杆菌感染的进展 易感BALB/c小鼠的皮肤到内脏部位是由 Th2、CD4+淋巴细胞亚群的扩增和IL-4的产生。 尽管干扰素-γ和Th1 CD4+细胞的发育是治愈所必需的 在耐药C57BL/6小鼠和经保护性治疗的BALB/c小鼠中 抗IL-4抗体，干扰素-伽玛治疗不能恢复疗效 BALB/c小鼠的免疫功能。根据我们的初步数据，我们建议 IL-12可能是Th2介导的一种更有效的免疫治疗剂 疾病。IL-12是一种异源二聚体T细胞生长和干扰素-γ B细胞和巨噬细胞产生的刺激性细胞因子 这是已知的促进Th1和抑制Th2细胞在体外的反应。 我们的初步研究证实了IL-12能够治愈易感 BALB/c小鼠，并在以下情况下持久抑制Th2免疫反应 在感染主要乳杆菌期间早期给药。治疗 具有抗IL-12抗体的耐药C57BL/6小鼠会加重疾病。 我们假设IL-12强烈抑制Th2 T细胞反应， 感染过程中IL-12合成和功能的抑制导致Th2- 介导的疾病进展，以及IL-12具有潜在的 利什曼病和其他Th2介导的免疫治疗剂 寄生虫病。我们建议进行实验以进一步探索基本的 白介素12在利什曼病中的产生和功能的生物学 确定在小鼠模型中的免疫治疗用途可能提示 临床应用。具体目标是： 1)研究IL-12在调节CD4+亚群选择中的作用 BALB/c小鼠的治疗性免疫及其耐药性 感染大利什曼原虫的C57BL/6小鼠。 2)确定BALB/c和BALB/c产生IL-12的差异 C57BL/6小鼠感染利什曼病。 3)开发IL-12作为免疫调节剂的治疗用途 在已确诊的利什曼病期间的反应。

The long-term goal of these studies is to understand cytokine-based mechanisms responsible for curative and noncurative immune responses during leishmaniasis. A well-characterized model of murine leishmaniasis has already provided important insights into the cytokine pathology of this disease. Progression of L. major infection from cutaneous to visceral sites in susceptible BALB/c mice is mediated by expansion of the Th2 CD4+ lymphocyte subset and production of IL-4. Although IFN-gamma and Th1 CD4+ cell development are necessary for cure in resistant C57BL/6 mice and in BALB/c mice protectively treated with anti-IL-4 antibodies, IFN-gamma therapy does not restore curative immunity in BALB/c mice. Based on our preliminary data, we propose that IL-12 may be a more effective immunotherapeutic agent for Th2-mediated illnesses. IL-12 is a heterodimeric T-cell growth and IFN-gamma stimulatory cytokine that is produced by B-cells and macrophages and that is known to promote Th1 and suppress Th2 cell responses in vitro. Our preliminary studies confirm the ability of IL-12 to cure susceptible BALB/c mice and to durably suppress Th2 immune responses when administered early during infection with L. major. Treatment of resistant C57BL/6 mice with anti-IL-12 antibodies exacerbates disease. We hypothesize that IL-12 strongly inhibits Th2 T cell responses, that suppression of IL-12 synthesis and function during infection causes Th2- mediated progression of disease, and that IL-12 has potential as an immunotherapeutic agent in leishmaniasis and other Th2-mediated parasitic diseases. We propose experiments to explore further the basic biology of IL-12 production and function during leishmaniasis and to identify immunotherapeutic uses in the mouse model that may suggest clinical applications. Specific aims are to: 1) Examine the role of IL-12 in regulating CD4+ subset selection and curative immunity in disease-susceptible BALB/c mice and resistant 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) Develop uses for IL-12 as a therapeutic modulator of immune responses during established leishmaniasis.