IL-12 in Leishmania infected human dendritic cells

描述（由申请人提供）：利什曼病是一种世界性疾病 在许多发展中国家造成了严重的发病率和死亡率。 利什曼原虫感染的临床表现差异很大， 从自愈性病变到致命的内脏疾病， 引发感染的利什曼原虫物种的差异。的事实 这些寄生虫表现出如此不同的毒力特征， 这个群体是一个很好的模型，以评估准确的贡献，主机 和寄生虫相关的特性在产生不同的病理中起作用。 研究利什曼原虫抗性的动物模型表明保护性免疫 需要产生CD 40/CD 40 L依赖的IL-12产生的Th 1 应答在感染过程中发生的初始事件为 随后的免疫反应。为了模拟利什曼原虫的最初事件 感染后，我们采用体外人树突状细胞（DC）系统， 传染期寄生虫我们以前证明，诱导的 这些细胞的IL-12是寄生虫物种依赖性的，并且需要CD 40 L 刺激.而感染导致内脏疾病的物种 （L. donovani）不引起CD 40 L依赖性IL-12产生的上调， 感染L.主要，一种与自限性皮肤 疾病，引发树突状细胞增加IL-23分泌。整体 这项建议的目标是确定负责的分子决定因素 这些不同的IL-12反应。存在两种可能性来解释这些 差异：1）L.主要的寄生虫有一些内在的能力， 用于IL-12产生的人DC，或2）用于产生IL-12的一般引发剂中的微生物刺激物， IL-23和L. Donovani寄生虫诱导一些下调级联反应， IL-12的CD 40 L刺激。为了验证这些假设，以下目标是 建议：具体目标1。为了鉴定DC分泌的产物， 利什曼原虫在IL-12调节中发挥作用。因素的归纳 利什曼原虫的诱导及其抑制或增强能力 将评估IL-12的产生。具体目标2。为了确定点 利什曼原虫属（Leishmania spp.）调节人DC中IL-12的产生。 将进行研究以确定是否阻断L. donovani感染的DC涉及转录或翻译调控。 具体目标3。鉴定调节IL-12诱导的因子 利什曼原虫介导利什曼原虫与宿主细胞的结合和侵入 通过特定的宿主细胞表面受体。这些具体的作用 利什曼原虫引发人DC产生IL-12中的受体将是 评估。还将开始研究以确定寄生虫因素 参与这个过程。能力的内在差异 利什曼原虫引发树突状细胞产生IL-12可能部分解释 利什曼病的愈合和非愈合形式的演变， 可以作为新的抗原或化学治疗靶点来对抗这种疾病， 毁灭性的疾病

DESCRIPTION (provided by applicant): Leishmaniasis is a cosmopolitan disease causing substantial morbidity and mortality in much of the developing world. The clinical manifestations of Leishmania infection vary substantially ranging from self-healing lesions to fatal visceral disease and are attributed to differences in the Leishmania species initiating the infections. The fact that these parasites exhibit such different virulence characteristics makes this group an excellent model to evaluate the precise contributions that host and parasite related properties play in generating different pathologies. Animal models studying resistance to Leishmania indicate protective immunity requires the generation of CD40/CD40L-dependent IL-12 generated Th 1 responses. The initIal events that occur during an infection set the tone for a subsequent immune response. To model the initial events of Leishmania infection, we employ an in vitro system of human dendritic cells (DC) and infectious stage parasites. We previously demonstrated that the induction of IL-12 by these cells is parasite species dependent and requires CD40L stimulation. Whereas infections with species responsible for visceral disease (L. donovani) cause no upregulation of CD40L-dependent IL-12 production, infection with L. major, a species associated with self-limiting cutaneous disease, primes dendritic cells for augmented IL-23 secretion. The overall goal of this proposal is to identify the molecular determinants responsible for these disparate IL-12 responses. Two possibilities exist to explain these differences: 1) L. major parasites have some intrinsic capacity to prime human DC for IL-12 production, or 2) microbial stimulus in general primes for IL-23 and L. donovani parasites induce some down-regulatory cascade to inhibit CD40L stimulation of IL-12. To test these hypotheses, the following aims are proposed: Specific Aim 1. To identify DC secreted products induced by Leishmania that play a role in IL-12 regulation. The induction of factors induced by Leishmania parasites and their inhibitory or enhancing capacities on IL-12 production will be assessed. Specific Aim 2. To determine the point of regulation that Leishmania spp. modulate IL-12 production in human DC. Studies will be performed to determine if the block on IL-12 secretIon in L. donovani- infected DC involves transcriptional or translational regulation. Specific Aim 3. Identification of the factor(s) that regulate IL-12 induction by Leishmania. Leishmania binding to and invasion of host cells is mediated via specific host cell surface receptors. The role of these specific receptors in Leishmania priming of human DC for IL-12 production will be assessed. Studies also will be initiated to identify the parasite factors involved in this process. The intrinsic differences in the ability of Leishmania to prime dendritic cells for IL-12 production partially may account for the evolution of healing and non-healing forms of leishmanial disease and may serve as novel antigens or chemotherapeutic targets to combat this devastating disease.