Modulation of schistosome development by T cell signals

血吸虫病是一种由血吸虫属血吸虫引起的寄生虫病，可能导致 全球约2亿人出现严重的肝脏、肠道和泌尿系统病变，导致 严重的发病率和死亡率。除了构成对生活在地球上的人们的主要公共卫生问题 在南美、非洲和亚洲的流行地区，血吸虫病也是美国人非常关注的问题。 服务人员、和平队工作人员和平民访问血吸虫病流行的地区。高 治疗后的再感染率和对少数有效药物产生抗药性的可能性 血吸虫病的化疗药物促使人们努力开发预防感染的疫苗。 和/或疾病。虽然还没有开发出有效的疫苗，但来自现场和实验室的证据 研究表明，CD4+T细胞反应将是由AFP诱导的反应的关键组成部分 有效的疫苗。然而，我们使用血吸虫感染的小鼠模型进行的研究表明 自相矛盾的是，血吸虫也需要宿主CD4+T细胞的信号来完成它们的发育 正常情况下，阻断寄生虫和宿主T细胞之间的相互作用可能会提供一种新的 干预寄生虫发育的方法。 我们研究的长期目标是为开发新的免疫疗法做出贡献 防止血吸虫在确定的人类宿主中发展，从而同时防止 与血吸虫感染和阻断寄生虫传播有关的病理学。的总体目标 这项研究是为了加深我们对CD4+T细胞在促进发育和治疗中的作用的理解。 血吸虫血吸虫的繁殖。这项研究的具体目的是(1)确定 仅有CD4*T细胞的存在就足以促进寄生虫的发展，(2)确定CD4+ T细胞对血吸虫抗原的反应是影响血吸虫结局的重要因素 以及(3)确定CD4+T细胞细胞因子白介素2(IL-2)在影响 血吸虫发育的结果。具体目标1将通过检查血吸虫来实现 在转基因小鼠模型中的感染，其中动物的CD4+T细胞都不能对 血吸虫抗原，因为它们对无关抗原的特异性有限。具体目标2将是 通过选择性地重建免疫缺陷小鼠，使其拥有可以或不能的CD4+T细胞 在感染前对血吸虫抗原做出反应，然后用 适当的抗原对寄生虫的发育。具体目标3将通过检查血吸虫来实现 IL-2缺陷小鼠的感染。

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.