Mucosal immune regulation in murine amebic colitis

描述(申请人提供)：阿米巴结肠炎是阿米巴病最常见的形式，阿米巴病是一种寄生虫病，每年导致100,000人死亡。人类和实验数据没有清楚地证明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型阿米巴结肠炎小鼠模型的工作证明了获得性免疫通过接种疫苗来保护免受侵袭的能力，以及CD4+T细胞在疾病发展中的有害作用。本研究计划着眼于后者，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调节失调的CD4+T细胞对寄生虫负担和肠道炎症的发展都有独立的作用。可能的机制包括IL-4介导的吞噬细胞抑制，肥大细胞的诱导，或失去调节的转化生长因子-b的产生。技术将包括用单抗在体内阻断关键的T辅助细胞因子，以及耗尽吞噬细胞和肥大细胞。C3HSCID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。这项工作由此架起了寄生虫生物学和粘膜免疫学领域的桥梁。在拟议研究计划的头两年，将进行寄生虫学和免疫学方面的严格正规培训。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，他们将指导该提案的实验室部分。此外，还将利用弗吉尼亚大学和美国农业部免疫学、胃肠病、传染病和病理学系的协作者和顾问组成的支持性网络。本研究提案中提出的培训和研究的综合方法将指导申请人实现其成为免疫寄生虫学独立调查员的目标。

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.