IL-12 AS AN IMMUNOPOTENTIATOR IN LEISHMANIASIS

利什曼病是一种慢性感染，可导致严重的毁容。 皮肤损害或致命的内脏疾病。化疗是唯一 在这种疾病中常用的治疗干预方法。这个 这种疗法的潜力是巨大的，因为主要的进展是 在我们对调节免疫系统的因素的理解中做出了贡献。 最显著的进步是对主要T助手的描述 控制免疫系统的细胞亚群，即CD4+Th1和Th2 细胞。对这些T细胞亚群是如何调节的理解 提供了对疾病状态进行干预并增强 适当的免疫反应。在利什曼病中，这一点已经确立。 在许多情况下，疾病的进展与以下两种情况有关 CD4+Th2细胞亚群的不适当扩张，或 CD4+Th1细胞的发育，它介导了保护。其中一个 影响Th1细胞扩增和功能的主要细胞因子是 IL-12。这种细胞因子诱导干扰素-γ，促进Th1细胞分化， 并优先扩展Th1子集。在拟议的研究中，一个 将利用皮肤利什曼病小鼠模型开发一种 基于免疫的疗法，将IL-12作为一种 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 一种预防和治疗疫苗的开发。要做到这一点 目标提出的第一系列研究是为了确定机制(S) IL-12通过其发挥作用。这些实验包括表征 内源性IL-12在利什曼原虫抗性中的作用 耐药小鼠和易感小鼠的比较研究和评价 与IL-12的反应相关的细胞和细胞因子 被用作免疫增强剂。然后我们将评估IL-1的能力- 12在治疗性疫苗中注射以诱导疾病消退。 第一系列研究将确定IL-12是否能抑制TH2细胞 在体外，以及哪些抑制剂(如单抗细胞因子 抗体)是Th1细胞扩增所必需的。届时将进行研究 直接解决使用IL-12逆转疾病发展的可能性 在治疗性疫苗中。还建议进行平行研究，以 确定IL-12是否能增强化疗的疗效。在一个 相关系列实验，我们将进一步定义最优 以IL-12为靶点诱导保护的条件 预防性疫苗中的免疫增强剂。这些实验将 勾画出诱导和扩展的最佳条件 保护性的CD4+Th1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.