HEPATIC TOLERIZATION OF THE CD8+ T CELL IMMUNE RESPONSE

说明(改编自应用程序) 应聘者有三年博士后研究经验，并将 很快就会完成他的肝病专科训练 胃肠病学。此K08导师奖的申请书与 为应聘者提供进一步经验和培训的目标 作为独立调查员在以下领域发挥作用是必要的 肝脏免疫学。该项目的长期目标是了解 导致肝脏T细胞反应不佳的机制。这是一个 制定策略以增强对病毒的免疫反应的先决条件 肝脏慢性感染，包括乙型和丙型病毒性肝炎。 我们和其他人已经证明，体内CD8+T细胞激活诱导T细胞 细胞死亡导致肝脏蓄积和CD8+T细胞的凋亡。这 从而导致假设肝脏是切除的特定部位 激活CD8+T细胞。初步数据显示，激活的CD8+T细胞 流经正常肝脏的细胞被ICAM-1依赖的细胞所保留 机制(肝内滞留)。保留的细胞与肝脏接触 巨噬细胞(Kupffer细胞)和部分细胞在14小时后发生凋亡 肝脏滞留的症状。候选人建议；1)确定 激活的CD8+T细胞在肝脏中正在发生凋亡。Ii)测试 CD8+T细胞在肝脏滞留过程中对枯否细胞的需求Iii) 确定肝脏中的特定多肽是否导致细胞分裂和凋亡 激活CD8+T细胞。四)确定肝内是否出现 骨髓来源细胞的肝细胞抗原诱导CD8+T细胞启动 或者是细胞凋亡。耶鲁大学的免疫生物学部门非常适合 培训是因为教师的质量，他们研究的广度， 他们作为导师的经验和耶鲁的核心设施。书院学派 医学部已承诺在此次培训期间为候选人提供受保护的时间。 在担任独立调查员之前的一段时间。

DESCRIPTION (adapted from the application) The candidate has three years post-doctoral research experience, and will be shortly be completing his subspecialty training in hepatology and gastroenterology. This application for the mentored K08 award is submitted with the goal of providing the candidate with the further experience and training necessary to function as an independent investigator working in the field of liver immunology. The project's long-term objectives are to understand the mechanisms which result in sub-optimal T cell responses in the liver. This is a prerequisite for developing strategies to enhance the immune response against chronic infections of the liver including viral hepatitis B and C. We and others have demonstrated that in-vivo CD8+ T cell activation induced T cell death results in liver accumulation and apoptosis of CD8+ T cells. This lead to the hypothesis that the liver is a specific site for the removal of activated CD8+ T cells. The preliminary data demonstrates that activated CD8+ T cells flowing through the normal liver are retained by an ICAM-1 dependent mechanism (hepatic retention). The retained cells are in contact with liver macrophages (Kupffer cells), and a proportion undergo apoptosis after 14 hours of hepatic retention. The candidate proposes to; 1) Establish the proportion of activated CD8+ T cells that are undergoing apoptosis in the liver. II) Test the requirement for Kupffer cells during hepatic retention of CD8+ T cells. III) Determine if specific peptide in the liver results in division and apoptosis of activated CD8+ T cell. IV) Determine if intra-hepatic presentation of hepatocyte antigens by bone marrow derived cells results in CD8+ T cell priming or apoptosis. The Section of Immunobiology at Yale University is ideal for training because of the quality of the faculty, the breadth of their research, their experience as mentors and the core facilities at Yale. The School of Medicine has pledged protected time for the candidate during this training period prior to functioning as an independent investigator.