CD40-CD154 Interactions in Cryptosporidial Immunity

CD40-CD154 在隐孢子虫免疫中的相互作用

• 批准号: 6450216
• 负责人: ESTHER M PONNURAJ
• 金额: $ 9.18万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6450216
• 关键词: AIDS; CD28 molecule; CD40 molecule; Cryptosporidium; T cell receptor; T lymphocyte; biological signal transduction; cell cell interaction; cellular immunity; cryptococcosis; dendritic cells; gene mutation; genetically modified animals; helper T lymphocyte; immunopathology; laboratory mouse; leukocyte activation /transformation; lymph nodes; major histocompatibility complex; microorganism immunology; parasite infection mechanism; parasitic gastrointestinal disorder

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.

描述（由申请人提供）：隐孢子虫Parvum（CP）原因 具有AIDS或突变CD154基因的人类长期和严重感染（X 与超级IGM或XHIM相关联的免疫缺陷导致硬化 胆管炎和肝衰竭。 CP感染了通常的肠道上皮细胞 结束其寿命被树突状细胞（DC）吞没在固有层中。这 该应用的基础假设是'CD40信号是必需的 CP将被DC杀死。该假设预测完整，可行，CP将 当没有CD40-CD154信号时，到达肠系膜淋巴结（MLN）。这 基本假设涉及表达CD4 T细胞的要求 CD 154和骨髓来源的CD40+细胞，使小鼠从CP中恢复 感染。它提出了一个问题：CD154+ CD4+ T细胞清除需要 CP必须特定于CP？我们发现表达转基因T的抹布 - / - 小鼠 卵蛋白（或细胞色素c）的细胞受体（TG）从CP感染中恢复。 我们的初步数据将表明，收养的DO11.10 T细胞是 在CP感染的抹布 - / - 小鼠的MLN中激活它们 MHC匹配的环境。我们的特定目标将确定是否e 关于XAI3转基因小鼠可以清除CP感染。这种方法测试 假设抗原肽将抗原肽的负载是A CP感染将从肠道中清除。 AIM 1下的次要方法将 （a）检验以下假设：转基因CD4细胞仅清除CP感染 他们选择的MHC环境。在LC中 用于激活TG和野生型CD4细胞的IL-12，B7和CD28将是 比较的。具体目标两个将检验固有椎板DCS的假设 需要CD40信号降解内吞的蛋白质和核酸 CP和上皮细胞。选择这些目标是因为它们解决了问题 对CP的免疫力和免疫病理学至关重要 当未消除感染时结果。 CP建立的机制 感染可能与其他重要细胞内有关 病原体，尤其是孢子虫和弓形虫。结果将是 对于寄生虫长期感染的免疫缺陷人类至关重要。