IL12 AS AN IMMUNOPOTENTIATOR IN LEISHMANIASIS

利什曼病是一种广泛传播并使人衰弱的原虫疾病。 还有动物。提高对猪瘟免疫学方面的认识 这种感染应该为新的治疗方法提供基础。我们建议 研究如何使用IL-12来促进血管生成 保护性免疫反应，特别侧重于发展 一种治疗慢性皮肤利什曼病的疫苗。实验 小鼠的感染在很大程度上模仿了临床 与人类疾病相关的演示文稿，并已用于 广泛研究利什曼病的免疫学反应。从这样的 研究表明，我们已经了解到了许多与 T细胞亚群的分化与调控。我们的假设是 在慢性利什曼病感染期间，小鼠对 IL-12，导致无法促进Th1型细胞的发育 免疫反应。我们将定义调节IL-12的因素 反应性，通过识别需要对IL-12做出反应的细胞 为了将T细胞群从Th2表型转变为Th1表型， 确定有效的IL-12对CD28-B7相互作用的要求 功能，并确定是什么调节IL-12受体在 利什曼原虫感染。我们的方法将是在体外操纵 体内细胞因子水平和共刺激相互作用促进 Th2亚群从主要感染乳杆菌感染的BALB/c小鼠向 一种保护性的Th1表型。我们将使用体外系统来定义 细胞和细胞因子参与转换，然后我们将验证我们的 体外研究与体内研究相结合。因为抗原反应细胞 很难跟踪，因为它们的频率在正常情况下很低(甚至 受感染的)动物，以及缺乏专门识别 在一些研究中，我们将使用来自OVA T细胞受体的细胞 (TCR)转基因小鼠(DO11.10)与OVA联合表达 L.主要寄生虫。梅杰对卵子蛋白的表达确立了这一点 作为模型寄生虫抗原，它会暴露在相同的 塑造T细胞对产生的其他抗原的反应的环境 作者L·梅杰。使用DO11.10 TCR转基因的另一个优势 小鼠对IL-12受体的调节由这些T细胞 研究得很好。我们将在体外应用从这些研究中获得的信息 研究设计促进Th1应答的最佳方法 使用治疗性疫苗感染主要乳杆菌感染的小鼠。

Leishmaniasis is a widespread and debilitating protozoal disease of man and animals. An improved understanding of the immunologic aspects of this infection should provide the basis for new therapies. We propose to study how IL-12 can be used to promote the development of a protective immune response, specifically focusing on the development of a therapeutic vaccine for chronic cutaneous leishmaniasis. Experimental infections in mice mimic to a large extent the spectrum of clinical presentations associated with human disease, and have been used extensively to study immunologic responses in leishmaniasis. From such studies we have learned a great deal about the factors involved in the differentiation and regulation of T cell subsets. Our hypothesis is that during chronic leishmanial infections mice are non-responsive to IL-12, leading to the inability to promote the development of a Th1-type immune response. We will define the factors that regulate IL-12 responsiveness, by identifying the cells that need to respond to IL-12 in order to shift a T cell population from a Th2 to a Th1 phenotype, defining the requirements for CD28-B7 interactions for effective IL-12 function, and determining what regulates the IL-12 receptor during Leishmania infection. Our approach will be to manipulate in vitro and in vivo levels of cytokines and costimulatory interactions to promote a shift in the Th2 population from L. major infected BALB/c mice towards a protective Th1 phenotype. We will use an in vitro system to define the cells and cytokines involved in switching, and we will then validate our in vitro findings with in vivo studies. Because antigen-reactive cells are difficult to track, due to their low frequency in a normal (or even infected) animal and the lack of reagents that specifically identify them, for some studies we will use cells from an OVA T cell receptor (TCR) transgenic mouse (DO11.10) in combination with an OVA expressing L. major parasite. The expression of OVA by L. major establishes this antigen as a model parasite antigen, that will be exposed to the same environment that shapes the T cell response to other antigens produced by L. major. An additional advantage to using DO11.10 TCR transgenic mice is that regulation of the IL-12 receptor by these T cells has been well studied. We will apply the information gained from these in vitro studies to design the best approach for promoting a Th1 response in infected L. major infected mice using a therapeutic vaccine.