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最常见的形式，是一种每年导致10万人死亡的寄生虫病。人体和实验数据尚未明确记录这种感染中保护性或有害获得性免疫的性质。我们最近使用C3H阿米巴结肠炎小鼠模型的工作已经证明了通过接种获得性免疫来防止定植的能力以及CD4+ T细胞在疾病发展中的有害作用。本研究计划旨在以后者为重点，明确CD4+ T细胞应答在疾病发病机制中的作用机制。我假设阿米巴结肠炎中CD4+ T细胞失调独立地促进了寄生虫负担和肠道炎症的发展。可能的机制包括IL-4介导的吞噬细胞抑制、肥大细胞诱导或失去调节性TGF-b的产生。技术将包括通过单克隆抗体在体内阻断关键的T辅助细胞因子和消耗吞噬细胞和肥大细胞。C3H SCID小鼠感染模型的开发将允许使用CD4+ T细胞及其亚群进行过继性转移实验，以测试抑制性和效应性CD4+ T细胞在结肠炎发展中的作用。因此，这项工作是寄生虫生物学和粘膜免疫学领域的桥梁。在拟议的研究计划的前两年，将进行寄生虫学和免疫学方面的严格正式培训。发起人和共同发起人，分别是分子寄生虫学和粘膜免疫学的研究人员，将指导该提案的实验室部分。此外，将利用整个弗吉尼亚大学和美国农业部的免疫学、胃肠病学、传染病和病理学部门的协作者和顾问组成的支助网络。本研究计划中提出的综合培训和研究方法将指导申请人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.