Transplantation is the ideal therapy for end stage heart and end stage kidney failure, but allograft survival and function remain suboptimal. This CTOT renewal application will build upon the findings resulting from the previous 4 years of studying biomarkers and mechanisms of injury in heart and kidney transplant recipients in an effort to develop therapies tailored to individual patients. The overriding clinical hypothesis is that specifically designed therapies guided by rationally chosen noninvasive immune monitoring will improve outcomes in heart and kidney transplant recipients. This hypothesis will be tested through 2 studies targeting 2 separate transplant populations. Study Concept 1 will test the hypothesis that the absence of anti-donor T cell memory will facilitate safe calcineurin inhibitor (CNI) elimination in nonsensitized, low risk recipients of kidney allografts. Recipients of living donor kidney allografts from 7 collaborating centers, without clinical acute rejection, donor-specific antibody or inflammation on protocol biopsy, and without evidence of anti-donor primed/memory T cells in their peripheral blood at 6 months will be randomized to tacrolimus elimination or remain on standard therapy. Renal function and histologic evidence of chronic injury at 24 months will be used as endpoints. The trial will be done within the established infrastructure built by us for the ongoing CTOT trials. The associated mechanistic studies will assess the impact of targeted anti- memory therapy including T cell depletion on the alloreactive effector T cell repertoire and will evaluate the molecular basis of allograft fibrosis in the presence or absence of tacrolimus. Study concept 2 will involve identifying heart transplant candidates at high risk for antibody mediated injury (high PRA) and performing a pilot study to determine the safety and efficacy of desensitization using a combination of B cell depletion (rituximab), IVIG plasmapheresis. The study will test the hypothesis that desensitization will lower PRA, diminish the waiting time to heart transplantation and result in acceptable 1 year graft survival and function. Patients will be enrolled from within a powerful consortium of 22 North American heart transplant centers that was developed for the ongoing heart transplantation CTOT05 study. Associated mechanistic studies will determine how the desensitization protocol impacts preformed alloreactive T and B cell immunity and will test the hypothesis that residual B and T cell immune memory with reactivity to donor antigens mediates post-transplant allograft injury. The proposed studies will address clinically relevant questions in kidney and heart transplantation and will provide novel information regardless of outcome.
Kidney transplantation and heart transplantation are lifesaving treatments for organ failure, but the transplanted organs do not last indefinitely. The goals of the proposed work are 1) to test new approaches for improving transplant outcomes (making organs last longer), 2) to identify modifiable risk factors to improve outcomes and 3) determine why the heart or kidney transplants fail so as to design better treatments.
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|D'Addio, Francesca; Vergani, Andrea; Potena, Luciano et al. (2018) P2X7R mutation disrupts the NLRP3-mediated Th program and predicts poor cardiac allograft outcomes. J Clin Invest 128:3490-3503|
|Asare, A; Kanaparthi, S; Lim, N et al. (2017) B Cell Receptor Genes Associated With Tolerance Identify a Cohort of Immunosuppressed Patients With Improved Renal Allograft Graft Function. Am J Transplant 17:2627-2639|
|Fishman, Jay A; Iklé, David N; Wilkinson, Robert A (2017) Discrepant serological assays for Pneumococcus in renal transplant recipients - a prospective study. Transpl Int 30:689-694|
|Weigt, S Samuel; Palchevskiy, Vyacheslav; Belperio, John A (2017) Inflammasomes and IL-1 biology in the pathogenesis of allograft dysfunction. J Clin Invest 127:2022-2029|
|Gandolfini, Ilaria; Harris, Cynthia; Abecassis, Michael et al. (2017) Rapid Biolayer Interferometry Measurements of Urinary CXCL9 to Detect Cellular Infiltrates Noninvasively After Kidney Transplantation. Kidney Int Rep 2:1186-1193|
|Crespo, Elena; Cravedi, Paolo; Martorell, Jaume et al. (2017) Posttransplant peripheral blood donor-specific interferon-? enzyme-linked immune spot assay differentiates risk of subclinical rejection and de novo donor-specific alloantibodies in kidney transplant recipients. Kidney Int 92:201-213|
|Menon, Madhav C; Murphy, Barbara; Heeger, Peter S (2017) Moving Biomarkers toward Clinical Implementation in Kidney Transplantation. J Am Soc Nephrol 28:735-747|
|Javaheri, Ali; Molina, Maria; Zamani, Payman et al. (2016) Cholesterol efflux capacity of high-density lipoprotein correlates with survival and allograft vasculopathy in cardiac transplant recipients. J Heart Lung Transplant 35:1295-1302|
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