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

项目摘要 这是一个K 08指导临床科学家研究职业发展奖博士的申请。 克莉丝汀林，一个肺病和重症监护医学医生和移植肺病学家， 丹佛的科罗拉多大学。林博士正在确立自己作为一名研究员在该领域的 移植免疫学，并获得K 08奖将为她提供必要的支持， 实现以下目标： 1巩固免疫学、生物统计学和基础科学研究设计的概念 2成为基础科学实验室技术和模型开发的专家 3发展独立的研究事业，目的是进一步发展基础科学和基础- 实体器官移植的转化研究，重点是慢性同种异体移植物功能障碍 为了实现这些目标，林博士将与移植领域的知名专家合作 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 排斥和移植耐受。他是科罗拉多中心的科学主任， 移植护理，研究和教育，并担任董事会的美国 移植协会。此外，她的建议的一个关键合作者是威廉·鲍德温博士， 病理学家和克利夫兰诊所勒纳研究所的慢性排斥反应方面的著名专家。 实体器官移植是终末期器官功能障碍患者的治疗选择， 提高了接受该手术的患者的存活率和生活质量。但其 “成功”受到慢性排斥反应发展的限制，慢性排斥反应是一种知之甚少的免疫介导的 这是移植后第一年后同种异体移植物丢失的最常见原因。林博士的 研究将集中于阐明慢性同种异体移植物的效应细胞和机制 在小鼠异位心脏移植中发现与慢性排斥反应相关的血管病变（CAV） 模型该提案中的假设围绕着这样的前提，即间接CD 4 + T细胞 通过激活两条独立的途径促进CAV：（1）通过驱动供体特异性 抗体（DSA）和（2）通过直接促进由先天免疫细胞介导的炎症。在 具体目标1，林博士将利用她以前开发的模型，以进一步扩大对角色的理解 的NK细胞和供体特异性抗体。在具体目标2中， 将探索间接CD 4 + T细胞和NK细胞/巨噬细胞。具体目标3将采用 调节性T细胞作为这种病症的可能治疗选择。这项研究将成为 在其他小鼠器官移植模型（肺）中的进一步研究，最终目标是转化 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.