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

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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.