Modulation of schistosome development by T cell signals

描述(申请人提供)：血吸虫病是一种由血吸虫属血吸虫引起的寄生虫病，在全球约2亿人中引起潜在的严重肝脏、肠道和泌尿系统病变，导致严重的发病率和死亡率。除了构成居住在南美、非洲和亚洲流行地区的人们的主要公共卫生问题外，血吸虫病也是美国服务人员、和平队工作人员和前往血吸虫病流行地区的平民的重大担忧。治疗后的高再感染率和对为数不多的有效血吸虫病化疗药物产生抗药性的可能性促使人们努力开发预防感染和/或疾病的疫苗。虽然尚未开发出有效的疫苗，但来自现场和实验室研究的证据表明，CD4+T细胞反应将是有效疫苗诱导的反应的关键组成部分。然而，我们使用小鼠血吸虫感染模型的研究表明，自相矛盾的是，血吸虫也需要宿主CD4+T细胞的信号来完成其正常发育，这表明阻断寄生虫与宿主T细胞之间的相互作用可能提供一种新的方法来干扰寄生虫的发育。我们研究的长期目标是帮助开发新的免疫疗法，旨在防止血吸虫在人类最终宿主中的发展，从而同时防止与血吸虫感染相关的病理变化，并阻止寄生虫的传播。这项研究的总体目的是为了加深我们对CD4+T细胞在促进血吸虫血吸虫发育和繁殖中所起作用的理解。这项研究的具体目的是(1)确定仅有CD4*T细胞的存在是否足以促进寄生虫的发育，(2)确定CD4+T细胞对血吸虫抗原的反应是否在影响血吸虫发育的结果中起重要作用，以及(3)确定CD4+T细胞细胞因子IL-2在影响血吸虫发育结果中的作用。具体目标1将通过在转基因小鼠模型中检查血吸虫感染来实现，在转基因小鼠模型中，动物的CD4+T细胞都不能对血吸虫抗原做出反应，因为它们对无关抗原的特异性有限。具体目标2将通过有选择地用感染前可以或不能对血吸虫抗原反应的CD4+T细胞重建免疫缺陷小鼠，然后检查用适当的抗原激活对寄生虫发育的影响。具体目标3将通过检查IL-2缺陷小鼠的血吸虫感染来实现。

DESCRIPTION (provided by applicant): Schistosomiasis, the parasitic disease caused by blood flukes of the genus Schistosoma, causes potentially serious liver, intestine and urinary system pathology in approximately 200 million people worldwide, resulting in significant morbidity and mortality. In addition to constituting a major public health concern for people living in endemic areas in South America, Africa and Asia, schistosomiasis is also a significant concern for U.S. service personnel, Peace Corps workers and civilians visiting regions where blood flukes are prevalent. High re-infection rates following treatment and the potential for development of resistance to the few effective chemotherapeutics for schistosomiasis has prompted efforts to develop vaccines that prevent infection and/or disease. While an effective vaccine has not yet been developed, evidence from field and laboratory studies indicate that CD4+ T cell responses will be critical components of the response induced by an effective vaccine. However, our studies using a murine model of schistosome infection have demonstrated that, paradoxically, schistosomes also require signals from host CD4+ T cells to complete their development normally, suggesting that blocking interactions between parasite and host T cells might provide a novel approach to interfering with parasite development. The long-term objective of our studies is to contribute to the development of new immunotherapies aimed at preventing schistosome development in the definitive human host, thus simultaneously preventing the pathology associated with schistosome infection and blocking parasite transmission. The overall aim of this study is to further our understanding of the role CD4+ T cells play in facilitating the development and reproduction of Schistosoma blood flukes. The specific aims of this study are (1) to determine whether the presence of CD4* T cells alone is sufficient to facilitate parasite development, (2) to determine whether CD4+ T cell responses to schistosome antigens are important in influencing the outcome of schistosome development, and (3) determine the role of the CD4+ T cell cytokine interleukin-2 (IL-2) in affecting the outcome of schistosome development. Specific aim 1 will be accomplished by examining schistosome infections in a transgenic mouse model where none of the animal's CD4+ T cells are able to respond to schistosome antigens because of their restricted specificity for an unrelated antigen. Specific aim 2 will be accomplished by selectively reconstituting immunodeficient mice with CD4+ T cells that can or cannot respond to schistosome antigens prior to infection and then examining the effect of activation with the appropriate antigen on parasite development. Specific aim 3 will be addressed by examining schistosome infection in IL-2-deficient mice.