IL-12 AS AN IMMUNOPOTENTIATOR IN LEISHMANIASIS

利什曼病是一种慢性感染，可导致严重毁容 皮肤病变或致命的内脏疾病。 化疗是唯一 通常用于治疗这种疾病。 的 这种治疗的潜力是极好的，因为主要的进展已经 我们对调节免疫系统的因素的理解。 最值得注意的进展是对主要的T辅助细胞的描述 控制免疫系统的细胞亚群，即CD 4 + Th 1和Th 2 细胞 了解这些T细胞亚群是如何调节的， 提供了干预疾病状态的潜力， 适当的免疫反应。 在利什曼病中， 在许多情况下，疾病的进展与 CD 4 + Th 2细胞亚群的不适当扩增，或 CD 4 + Th 1细胞的发展，介导保护作用。 之一 影响Th 1细胞扩增和功能的主要细胞因子是 IL-12。 这种细胞因子诱导IFN-γ，增强Th 1细胞分化， 并优先扩增Th 1亚群。 在拟议的研究中， 将使用皮肤利什曼病的鼠模型来开发一种 基于免疫学的疗法，将IL-12作为 免疫增强剂。 这些研究旨在评估基本的 IL-12生物学的问题，并将这些信息应用于 开发预防性和治疗性疫苗。 实现这一 目标第一系列研究建议是确定机制 IL-12的作用机制 这些实验包括表征 内源性IL-12在抗利什曼原虫感染中作用 在抗性和易感小鼠中进行的比较研究，以及评价 与IL-12反应相关的细胞和细胞因子， 用作免疫增强剂。 我们将评估IL的能力， 12在治疗性疫苗中施用以诱导疾病消退。 第一系列研究将确定IL-12是否可以抑制TH 2细胞 在体外，什么样的抑制剂（如单克隆抗细胞因子 抗体）是Th 1细胞扩增所必需的。 研究将 直接解决使用IL-12逆转疾病发展的潜力 一种治疗性疫苗。 还建议进行平行研究， 确定IL-12是否可以增强化疗的疗效。 中 相关的一系列实验，我们将进一步确定最佳 使用IL-12作为免疫抑制剂诱导保护的条件 预防性疫苗中免疫增强剂。 这些实验将 描绘诱导和扩张的最佳条件， 保护性CD 4 + Th 1细胞。

Leishmaniasis is a chronic infection that can cause severe disfiguring cutaneous lesions or fatal visceral disease. Chemotherapy is the only commonly practiced therapeutic intervention in this disease. The potential for such therapy is excellent, since major advances have been made in our understanding of the factors that regulate the immune system. The most notable advance has been the description of the major T helper cell subsets that control the immune system, namely CD4+ Th1 and Th2 cells. The understanding of how these T cell subsets are regulated has provided the potential to intervene in the disease state and potentiate appropriate immune responses. In leishmaniasis it is well established that disease progression in many cases is related to either the inappropriate expansion of the CD4+ Th2 cell subset, or a deficit in the development of CD4+ Th1 cells, which mediate protection. One of the principle cytokines that influences Th1 cell expansion and function is IL-12. This cytokine induces IFN-y, enhances Th1 cell differentiation, and preferentially expands the Th1 subset. In the proposed studies, a murine model of cutaneous leishmaniasis will be employed to develop an immunologically based therapy that incorporates IL-12 as an immunopotentiator. These studies are designed to evaluate basic questions of IL-12 biology, and apply that information towards the development of a prophylactic and therapeutic vaccine. To achieve this goal the first series of studies proposed is to define the mechanism(s) by which IL-12 functions. These experiments include characterization of the role of endogenous IL-12 in resistance to Leishmania major by comparative studies in resistant and susceptible mice, and an evaluation of the cells and cytokines associated with the response to IL-12 when it is used as an immunopotentiator. We will then assess the ability of IL- 12 administered in a therapeutic vaccine to induce resolution of disease. The first series of studies will determine if IL-12 can inhibit TH2 cells in vitro, and what inhibitors (such as monoclonal anti-cytokine antibodies) are required for expansion of Th1 cells. Studies will then directly address the potential to reverse disease development using IL-12 in a therapeutic vaccine. Parallel studies are also proposed to determine if IL-12 can augment the efficacy of chemotherapy. In a related series of experiments we will further define the optimal conditions for induction of protection using IL-12 as an immunopotentiator in a prophylactic vaccine. These experiments will delineate the optimal conditions for induction and expansion of protective CD4+ Th1 cells.