CD40-CD154 Interactions in Cryptosporidial Immunity

描述（由申请方提供）：隐孢子虫（CP）引起 艾滋病或CD 154基因突变的人类长期和严重感染（X 与高IgM相关的免疫缺陷，或XHIM）导致硬化 胆管炎和肝功能衰竭CP感染肠道上皮细胞， 结束它们被固有层中的树突状细胞（DC）吞噬的寿命。的 本申请的基本假设是“CD 40信号对于 CP将被DC杀死。这一假说预测，完整的，可行的，CP将 当没有CD 40-CD 154信号时，到达肠系膜淋巴结（MLN）。的 基本假设解释了表达CD 4 T细胞的需要， CD 154和骨髓来源的CD 40+细胞，用于小鼠从CP中恢复 感染这就提出了一个问题：CD 154 + CD 4 + T细胞是否需要清除 CP必须是CP特定的？我们发现表达转基因T细胞的RAG-/-小鼠 卵清蛋白（或细胞色素c）的细胞受体（Tg）从CP感染中恢复。 我们的初步数据将显示，过继转移的DO11.10 T细胞是 在CP感染的RAG-/-小鼠的MLN中激活，条件是它们处于 MHC匹配的环境。我们的具体目标之一将决定是否E 约xAI 3转基因小鼠可清除CP感染。这种方法测试了 假设抗原肽装载到自身MHC上是免疫应答所必需的， CP感染从肠道中清除。目标1之下的次级办法将 (a)测试转基因CD 4细胞只清除CP感染的假设， 他们被选择的MHC环境。在LC中， 用于活化Tg和野生型CD 4细胞的IL-12、B7和CD 28将被 比较了具体目标二将检验固有层DC 需要CD 40信号来降解内吞的蛋白质和核酸。 CP和上皮细胞。之所以选择这些目标，是因为它们解决了 对于理解CP免疫和免疫病理学至关重要， 当感染没有被根除的时候。国家方案建立的机制 感染可能与其他重要的细胞内 病原体，特别是微孢子虫和弓形虫。结果将是 对长期感染寄生虫的免疫缺陷的人很重要。

DESCRIPTION (Provided by the applicant): Cryptosporidium parvum (CP) causes prolonged and severe infections in humans with AIDS or mutated CD154 genes (X linked immunodeficiency with hyper IgM, or XHIM) leading to sclerosing cholangitis and liver failure. CP infects gut epithelial cells that normally end their lifespan engulfed by dendritic cells (DC) in the lamina propria. The hypothesis underlying this application is that 'a CD40 signal is necessary for CP to be killed by DC'. This hypothesis predicts that intact, viable, CP will reach the mesenteric lymph node (MLN) when there is no CD40-CD154 signal. The underlying hypothesis accounts for the requirement for CD4 T cells that express CD 154, and marrow-derived CD40+ cells, for mice to recover from a CP infection. It raises the question: do the CD154+ CD4+ T cells required to clear CP have to be CP-specific? We found that RAG-/- mice expressing transgenic T cell receptors (Tg) for ovalbumin (or cytochrome c) recover from CP infections. Our preliminary data will show that adoptively transferred DO11.10 T cells are activated in the MLN of CP-infected RAG-/- mice provided that they are in an MHC matched environment. Our Specific aim one will determine whether E aboutxAI3 transgenic mice can clear a CP infection. This approach tests the hypothesis that the loading of antigen peptides onto self-MHC is required for a CP infection to be cleared from the gut. Secondary approaches under Aim 1 will (a) test the hypothesis that transgenic CD4 cells clear CP infections only in the MHC environment in which they were selected. In lc the requirements for IL-12, B7 and CD28 for activation of Tg and wild type CD4 cells will be compared. Specific Aim two will test the hypothesis that lamina propria DCs require a CD40 signal to degrade the proteins and nucleic acids of endocytosed CP and epithelial cells. These aims are selected because they address issues critical for under- standing immunity to CP and the immunopathology that results when an infection is not eradicated. Mechanisms established in CP infections are likely to be relevant to other important intracellular pathogens, particularly Microsporidia and Toxoplasmah sp. The results will be important for immunodeficient humans chronically infected with the parasite.