Mucosal immune regulation in murine amebic colitis

描述（由申请人提供）：阿米巴结肠炎是阿米巴病的最常见形式，阿米巴病是一种寄生虫病，每年造成10万人死亡。人类和实验数据还没有清楚地证明在这种感染中保护性或有害的获得性免疫的性质。我们最近使用阿米巴结肠炎的C3H小鼠模型的工作已经证明了获得性免疫通过疫苗接种保护免受定植的能力以及CD4 + T细胞在疾病发展中的有害作用。本研究计划旨在关注后者，以确定疾病发病机制中CD4 + T细胞反应的机制。我推测阿米巴结肠炎中失调的CD4 + T细胞独立地促进寄生虫负荷和肠道炎症的发展。可能的机制包括IL-4介导的吞噬细胞抑制、肥大细胞诱导或调节性TGF-β产生的丧失。技术将包括通过单克隆抗体在体内阻断关键的T辅助细胞因子以及吞噬细胞和肥大细胞的耗竭。C3H SCID小鼠感染模型的开发将允许使用CD4 + T细胞及其亚群的过继转移实验，以测试抑制性与效应性CD4 + T细胞对结肠炎发展的作用。 因此，这项工作在寄生虫生物学和粘膜免疫学领域架起了桥梁。严格的正规培训，寄生虫学和免疫学将发生在头2年的拟议研究计划。申办者和共同申办者（分子寄生虫学和粘膜免疫学研究者）将分别指导提案的实验室部分。此外，还将利用弗吉尼亚大学和美国农业部免疫学、胃肠病学、传染病和病理学系的合作者和顾问的支持网络。本研究提案中提出的培训和研究综合方法将指导申请人实现成为免疫寄生虫学独立研究者的目标。

DESCRIPTION (provided by applicant): Amebic colitis is the most common form of amebiasis, a parasitic disease that accounts for 100,000 annual deaths. Human and experimental data have not clearly documented the nature of protective or deleterious acquired immunity in this infection. Recent work of ours using a C3H mouse model of amebic colitis has documented the capacity for acquired immunity to protect against colonization through vaccination as well as a deleterious role for CD4+ T cells in the development of disease. This research plan aims to focus on the latter, to define the mechanism of the CD4+ T cell response in disease pathogenesis. I hypothesize that dysregulated CD4+ T cells in amebic colitis contribute independently to both parasite burden and the development of intestinal inflammation. Possible mechanisms include IL-4 mediated phagocyte inhibition, mast cell induction, or loss of regulatory TGF-b production. Techniques will include in vivo blockade of key T helper cytokines by monoclonal antibody and depletion of phagocytes and mast cells. Development of the C3H SCID mouse model of infection will allow adoptive transfer experiments using CD4+ T cells and subsets therein to test the role of suppressor versus effector CD4+ T cells on the development of colitis. The work thus bridges the fields of parasite biology and mucosal immunology. Rigorous formal training in parasitology and immunology will occur during the first 2 years of the proposed research plan. The sponsor and cosponsor, investigators in molecular parasitology and mucosal immunology, respectively, will guide the laboratory component of the proposal. Additionally a supportive network of collaborators and consultants will be utilized from the departments of Immunology, Gastroenterology, Infectious Disease and Pathology throughout the University of Virginia and the United States Department of Agriculture. The comprehensive approach in training and research laid out in this research proposal will guide the applicant towards his goal of being an independent investigator in immunoparasitology.