Improving long-term allograft survival in kidney transplantation by targeting B cell survival cytokines

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PROJECT SUMMARY/ABSTRACT The proposal presents a four-year career development program designed to provide Sarah Panzer, MD, an Assistant Professor at the University of Wisconsin-Madison, the career development and research experiences necessary to become an independent physician scientist to improve patient and allograft survival of kidney transplant recipients. Approximately 50% of transplanted kidneys fail within 10 years of transplantation. The major pathologic diagnosis in failing kidney allografts is transplant glomerulopathy (TG). While TG has largely been attributed to chronic antibody-mediated rejection (cABMR), the key mediators of this process remain unknown and no effective therapeutics exist. In a multitude of B cell mediated diseases, the B cell survival cytokines have been demonstrated to exacerbate disease activity and represent a viable therapeutic target. In kidney transplantation, preliminary studies have found elevated levels of B cell survival cytokines in the serum and kidney tissue of patients with cABMR. The hypothesis of this proposal is B cell survival cytokines play pivotal roles in promoting the development of TG and predict allograft failure. This proposal will test this hypothesis via 1) deficiency of B cell cytokines in an animal kidney transplant model to attenuate TG, 2) determination of the ability of intragraft B cell cytokines to predict allograft failure in prevalent TG patients, and 3) determination of B cell survival cytokines as a risk factor for incident TG in a prospective observational cohort of high-risk kidney transplant patients. These data will support future R01 funded study to investigate B cell survival cytokines in TG as a therapeutic target. As a junior faculty member at an institution with extensive infrastructure to support early stage investigators and a highly active transplant center, Dr. Panzer is in an ideal environment to complete the proposed research and pursue advanced training. Her career development plan includes both coursework and mentored research training in the areas of clinical study design, subject recruitment and retention, and survival analysis. To ensure success, she has identified committed, expert mentors and secured protected time for this work. This award addresses a significant gap in the field of kidney transplantation while affording the mentored research experience critical for Dr. Panzer to become a successful physician scientist leading a program to improve outcomes in kidney transplantation.