Divergent Pathways of Indirect CD4 + T Cell Dependent Chronic Allograft Dysfunction

项目摘要 这是一份K08临床科学家导师研究职业发展奖的申请表。 克里斯汀·林，肺部疾病和重症监护内科医生和移植肺病学家 科罗拉多大学丹佛分校。林博士正在将自己确立为一名研究人员 移植免疫学，并获得K08奖将为她提供必要的支持，以 实现以下目标： 1巩固免疫学、生物统计学和基础科学研究研究设计的概念 成为基础科学实验室技术和模型开发方面的专家 3发展独立的研究事业，目标是进一步发展基础科学和基础-- 以慢性同种异体移植功能障碍为中心的实体器官移植的翻译研究 为了实现这些目标，林博士将与移植领域的一位知名专家合作 免疫学，她的导师罗纳德·吉尔博士。吉尔博士的研究重点是急性同种异体移植的机制 排斥反应和移植耐受。他是科罗拉多州研究中心的科学主任 移植护理、研究和教育，并担任美国 移植学会。此外，她提案的关键合作者是威廉·鲍德温博士，他是 克利夫兰临床勒纳研究所的病理学家和著名的慢性排斥反应专家。 实体器官移植是终末期器官功能障碍患者的首选治疗方法， 提高接受这种手术的患者的存活率和生活质量。然而，它的 “成功”受到慢性排斥的发展的限制，慢性排斥是一种鲜为人知的免疫调节机制。 这一过程是移植后第一年后同种异体移植物丢失的最常见原因。林医生的 研究将集中在阐明慢性同种异体移植的效应细胞(S)和机制(S) 小鼠异位心脏移植中与慢性排斥反应相关的血管病变(CAV) 模特。这项提议中的假设围绕着这样一个前提，即间接CD4+T细胞 通过激活两条独立的通路促进CAV：(1)通过驱动供体特异性的产生 抗体(DSA)和(2)通过先天免疫细胞直接促进炎症反应。在……里面 具体目标1，林博士将利用她之前开发的模型来进一步扩大对角色的理解 CAV中NK细胞和供体特异性抗体的表达。在具体目标2中， 将探索间接的CD4+T细胞和NK细胞/巨噬细胞。然后，特定目标3将雇用 调节性T细胞是治疗这种疾病的一种可能的选择。这项研究将构成 进一步研究其他小鼠器官移植模型(肺)，最终目标是翻译 这一建议的结果也适用于患者的研究。

Project Abstract This is an application for a K08 Mentored Clinical Scientist Research Career Development Award for Dr. Christine Lin, a pulmonary disease and critical care medicine physician and transplant pulmonologist at the University of Colorado, Denver. Dr. Lin is establishing herself as an investigator in the field of transplantation immunology, and receipt of a K08 award will provide her with the support necessary to accomplish the following goals: 1 Solidify concepts in immunology, biostatistics, and basic science research study design 2 Become an expert in basic science laboratory techniques and model development 3 Develop an independent research career, with the aim of further basic science and basic- translational research in solid organ transplantation with a focus on chronic allograft dysfunction To achieve these goals, Dr. Lin will be working with a well-known expert in the field of transplantation immunology, her mentor Dr. Ronald Gill. Dr. Gill's research focuses on mechanisms of acute allograft rejection and transplantation tolerance. He is the Scientific Director of the Colorado Center for Transplantation Care, Research and Education and serves on the Board of Directors of the American Society of Transplantation. In addition, a key collaborator on her proposal is Dr. William Baldwin, a pathologist and noted expert in chronic rejection at the Cleveland Clinic Lerner Research Institute. Solid organ transplantation is the treatment of choice for patients with end-stage organ dysfunction, increasing survival and improving quality of life for patients that undergo this procedure. However, its “success” is limited by the development of chronic rejection, a poorly understood, immune-mediated process that is the most common cause of allograft loss after the first post-transplant year. Dr. Lin's research will focus on elucidating the effector cell(s) and mechanism(s) underlying chronic allograft vasculopathy (CAV), the cardiac correlate of chronic rejection, in a mouse heterotopic heart transplant model. The hypotheses within this proposal center around the premise that indirect CD4+ T cells facilitate CAV through activation of two separate pathways: (1) by driving generation of donor-specific antibody (DSA) and (2) by directly facilitating inflammation mediated by innate immune cells. In Specific Aim 1, Dr. Lin will utilize her prior developed model to further expand understanding of the role of NK cells and donor-specific antibodies in CAV. In Specific Aim 2, the direct interactions between indirect CD4+ T cells and NK cells / macrophages will be explored. Specific Aim 3 will then employ regulatory T cells as a possible therapeutic option for this condition. This research will form the basis of further investigation in other mouse organ transplant models (lung), with the eventual goal of translating the results of this proposal to studies in patients as well.