Intestinal Cytokines in Cryptosporidiosis

描述(申请人提供)：微小隐孢子虫是一种主要的 世界范围内腹泻的原因，没有可靠的抗寄生虫药 心理治疗。在免疫能力强的人中，微小弧菌感染会导致 自限性腹泻病。相比之下，艾滋病患者可能会发展为慢性 腹泻，这可能是致命的。有效的抗逆转录病毒治疗可以导致 艾滋病相关隐孢子虫病的解决，可能是由于病情改善 在肠道免疫反应中。这个项目的长期目标是 确定控制隐孢子虫病的免疫机制 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、有免疫能力的志愿者表达干扰素 γ(IFNT)对微小弧菌暴露反应，且IFN7的表达是 与抵抗感染有关。相比之下，天真的，有症状的 个体最初表达的白介素15(IL-15)与 控制卵囊排泄。未检测到IL-15和IFN7 艾滋病相关的慢性隐孢子虫病，但IL-15和IFN7的表达 在对抗逆转录病毒治疗有反应的患者的活组织检查中注意到。 初步研究表明，IL-15可激活淋巴细胞裂解 被感染的上皮细胞。然而，许多问题仍然存在。例如，什么 是IL-15和IFNGamma在控制阶段使用的效应器机制 这些应对措施是如何协调一致的？Th1细胞因子真的能导致 艾滋病患者在缺乏免疫的情况下隐孢子虫病的解决 恢复？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。《公约》的具体目标 目前的建议是：1)检验IL-15和IFNGamma有助于 通过激活细胞溶解细胞和清除上皮细胞感染 建立效应器细胞使用的机制。2)确认 Th1细胞因子在隐孢子虫病治疗中的重要性 IL-12治疗慢性阻塞性肺疾病的试点、概念验证、开放标签试验 艾滋病患者对抗逆转录病毒治疗无效的隐孢子虫病。3) 为了确认目标1和目标1中定义的细胞溶解细胞使用的机制 相关的细胞因子、效应分子和趋化因子在 肠道微阵列技术在人类隐孢子虫病肠道中的应用 免疫活性实验挑战前后的活组织检查 患有微小隐孢子虫卵囊的成虫。4)检验艾滋病患者的假设 患有隐孢子虫病的患者依次表达先天记忆，然后是Th1记忆 免疫重建过程中的反应。这些研究应该确定关键 预防疫苗所需的人类免疫反应的几个方面 隐孢子虫病，并确定可针对的宿主反应 艾滋病等患者隐孢子虫病的辅助免疫治疗 免疫缺陷。这些结果还应该为我们提供对 粘膜免疫机制涉及对其他细胞内病原体的免疫。

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.