Intestinal Cytokines in Cryptosporidiosis

描述（由申请人提供）：隐孢子虫是一种主要的 全球腹泻的原因，没有可靠的抗寄生虫药 疗法在免疫功能正常的个体中，C.细小病毒感染导致 自限性慢性病相比之下，艾滋病患者可能会出现慢性 腹泻可能致命有效的抗逆转录病毒治疗可导致 AiDS相关隐孢子虫病的消退，可能是由于改善 在肠道免疫反应中。该项目的长期目标是 确定参与隐孢子虫病控制的免疫机制， 健康成人和艾滋病患者接受有效的抗逆转录病毒治疗。我们有 证明致敏的免疫活性志愿者表达干扰素， γ-干扰素（IFNT）对C.暴露于细小病毒， 与抵抗感染有关。相比之下，天真，症状 个体最初表达白细胞介素15（IL-15）， 控制卵囊排泄。IL-15和IFN-7均未检测到。 艾滋病相关的慢性隐孢子虫病，但IL-15和IFN-7的表达， 在从抗逆转录病毒治疗有反应的患者获得的活组织检查中注意到。 初步研究表明，IL-15可以激活淋巴细胞溶解， 感染的上皮细胞然而，许多问题仍然存在。比如什么 是IL-15和IFN γ在对照阶段使用的效应机制， 这些反应是如何协调的？Thl细胞因子实际上是否可以导致 艾滋病患者隐孢子虫病在免疫缺乏的情况下的解决 康复？艾滋病患者免疫应答的顺序是什么 通过有效的抗逆转录病毒治疗恢复。该委员会的具体目标 目前的建议是：1）测试IL-15和IFN γ有助于 通过活化溶细胞细胞清除上皮细胞感染， 建立效应细胞使用的机制。2)确认 Th 1细胞因子在隐孢子虫病治疗中重要性 IL-12治疗慢性炎症的初步、概念验证、开放标签试验 抗逆转录病毒治疗无效的艾滋病患者的隐孢子虫病。第三章 为了证实aim 1和aim 2中定义的溶细胞细胞使用的机制， 相关的细胞因子、效应分子和趋化因子在细胞中表达。 肠道微阵列分析人类隐孢子虫病肠道微阵列分析 在免疫活性细胞实验激发前后获得的活检 成年人C.小卵囊4)为了验证艾滋病患者 隐孢子虫病依次表达先天记忆和Thl记忆 免疫重建过程中的反应。这些研究应确定关键的 疫苗所需的人类免疫反应方面， 隐孢子虫病，并确定宿主的反应，可以针对 艾滋病等隐孢子虫病的免疫治疗 免疫缺陷研究结果还应提供有关 参与粘膜对其他细胞内病原体的免疫机制。

DESCRIPTION (Provided by the applicant): Cryptosporidium parvum is a major cause of diarrhea worldwide, for which there is no reliable antiparasitic therapy. In immunocompetent individuals, C. parvum infection results in a self-limited diarrheal illness. By contrast, AIDS patients may develop chronic diarrhea, which can be fatal. Effective antiretroviral therapy can lead to resolution of AiDS-associated cryptosporidiosis, presumably due to improvement in the intestinal immune response. The long-term goals of this project are to determine the immune mechanisms involved in the control of cryptosporidiosis in healthy adults and AIDS patients on effective antiretroviral treatment. We have demonstrated that sensitized, immunocompetent volunteers expressed interferon gamma (IFNT) in response to C. parvum exposure and that IFN7 expression was associated with resistance to infection. By contrast, naive, symptomatic individuals initially expressed Interleukin 15 (IL-15), which was associated with control of oocyst excretion. Neither IL-15 nor IFN7 was detected in AIDS-associated chronic cryptosporidiosis, but expression of IL-15 and IFN7 was noted in biopsies obtained from patients responding to antiretroviral therapy. Preliminary studies demonstrated that IL-15 can activate lymphocytes to lyse infected epithelial cells. However, many questions remain. For example, what are the effector mechanisms used by IL-15 and IFNgamma, in the control phase and how are these responses coordinated? Can Thl cytokines in fact lead to resolution of cryptosporidiosis in AIDS patients in the absence of immune recovery? What is the sequence of responses in AIDS patients with immune recovery with effective anti-retroviral therapy. The specific aims of the current proposal are: 1 ) To test the hypothesis that IL-15 and IFNgamma help clear infection of epithelial cells by activation of cytolytic cells and establish the mechanisms used by the effector cells. 2) To confirm the importance of Thl cytokines in resolution of cryptosporidiosis by conducting a pilot, proof-of-concept, open-label trial of IL-12 therapy in chronic cryptosporidiosis in AIDS patients not responding to antiretroviral therapy. 3) To confirm that mechanisms used by cytolytic cells defined in aim 1 and associated cytokines, effector molecules, and chemokines are expressed in the intestines in human cryptosporidiosis using microarray analysis of intestinal biopsies obtained before and after experimental challenge of immunocompetent adults with C. parvurn oocysts. 4) To test the hypothesis that AIDS patients with cryptosporidiosis sequentially expresses innate and then Thl memory responses during immune reconstitution. These studies should identify key aspects of the human immune response needed for vaccines to prevent cryptosporidiosis and identify the host responses that can be targeted for adjunctive immunotherapy for cryptosporidiosis in patients with AIDS and other immunodeficiencies. The results should also provide insights into the mechanisms involved in mucosal immunity to other intracellular pathogens.