Modulation of schistosome development by T cell signals

描述（由申请人提供）：血吸虫病是由血吸虫属血吸虫引起的寄生虫病，在全世界约2亿人中引起潜在的严重肝脏、肠道和泌尿系统病变，导致显著的发病率和死亡率。除了构成生活在南美洲、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、和平队工作人员和访问血吸虫流行地区的平民的重要问题。治疗后的高再感染率和对血吸虫病的少数有效化疗药物产生耐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，但来自田间和实验室研究的证据表明，CD 4 + T细胞应答将是有效疫苗诱导的应答的关键组成部分。然而，我们使用血吸虫感染小鼠模型的研究表明，自相矛盾的是，血吸虫也需要来自宿主CD 4 + T细胞的信号才能正常完成其发育，这表明阻断寄生虫和宿主T细胞之间的相互作用可能提供一种干扰寄生虫发育的新方法。我们研究的长期目标是促进新的免疫疗法的开发，旨在预防最终人类宿主中的寄生虫发展，从而同时预防与寄生虫感染相关的病理学并阻断寄生虫传播。本研究的总体目的是进一步了解CD 4 + T细胞在促进血吸虫血吸虫发育和繁殖中的作用。本研究的具体目的是（1）确定单独存在的CD 4 + T细胞是否足以促进寄生虫发育，（2）确定CD 4 + T细胞对寄生虫体抗原的应答是否在影响寄生虫体发育的结果中是重要的，以及（3）确定CD 4 + T细胞细胞因子白细胞介素-2（IL-2）在影响染色体发育结果中的作用。具体目标1将通过检查转基因小鼠模型中的溶酶体感染来实现，其中动物的CD 4 + T细胞都不能对溶酶体抗原应答，因为它们对不相关抗原的特异性有限。具体目标2将通过用CD 4 + T细胞选择性地重建免疫缺陷小鼠来实现，所述CD 4 + T细胞在感染前可以或不能对寄生虫抗原应答，然后检查用适当抗原活化对寄生虫发育的影响。具体目标3将通过检查IL-2缺陷小鼠中的溶酶体感染来解决。

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.