Transplantation is widely recognized as the treatment of choice for end stage organ failure. While short-term allograft survival has been steadily improving, long-term survival is still not optimal. Most grafts will eventually cease to function, primarily due to chronic allograft rejection. This application is based on two primary hypotheses. The first hypothesis is that T cell recognition of alloantigen, costimulation and subsequent activation plays a critical role in orchestrating the alloimmune response responsible for initiation and progression of chronic allograft rejection. The corollary hypothesis is that inhibiting T cell activation by T cell costimulatory blockade should prevent progression of chronic organ dysfunction following transplantation. The second hypothesis is that humoral immune responses play an important role in promoting chronic rejection and subsequent graft dysfunction. Therefore, targeting B cells and inhibition of further alloantibody production in transplant recipients who develop de novo anti-HLA alloantibodies early after transplantation should prevent the progression of organ dysfunction and improve long-term outcome. The overall goal of this application is to develop novel therapies for prevention and interruption of progression of chronic allograft dysfunction. As required by the CTOT-RFA we will propose to establish a consortium between the Harvard Transplant Centers and the University of California San Francisco Transplant Program to test two different approaches: the first one is a multi-organ approach and the second is an organ-specific one. In the multi-organ protocol we will test the hypothesis that B7 costimulation blockade (with LEA29Y) will block ongoing alloimmune responses and allow withdrawal of calcineurin inhibitors in renal and cardiac transplant recipients leading to prevention of progression of chronic allograft dysfunction and improvement in renal function. In the organ-specific protocol we will test the hypothesis that B cell depletion by anti-CD20 (Rituximab) in renal allograft recipients who develop early de novo anti-HLA alloantibodies will result in inhibition of antibody production, attenuation of humoral rejection and improvement of renal transplant function and pathological changes of chronic allograft nephropathy. All three trials will be accompanied by extensive mechanistic studies involving sensitive and specific assays, including peripheral cellular/humoral assays and intragraft molecular assays for expression patterns of alloimmune activation and effector function markers. The main goal of these studies is to understand the mechanisms of action of B7 blockade and B cell depletion in vivo, and to develop a set of surrogate markers of chronic allograft rejection in organ transplant recipients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI063623-03
Application #
7117837
Study Section
Special Emphasis Panel (ZAI1-PA-I (S2))
Program Officer
Bridges, Nancy D
Project Start
2004-09-01
Project End
2009-08-31
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
3
Fiscal Year
2006
Total Cost
$3,287,345
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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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
Starling, R C; Stehlik, J; Baran, D A et al. (2016) Multicenter Analysis of Immune Biomarkers and Heart Transplant Outcomes: Results of the Clinical Trials in Organ Transplantation-05 Study. Am J Transplant 16:121-36
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
Batal, Ibrahim; De Serres, Sacha A; Safa, Kassem et al. (2015) Dendritic Cells in Kidney Transplant Biopsy Samples Are Associated with T Cell Infiltration and Poor Allograft Survival. J Am Soc Nephrol 26:3102-13
Rychert, Jenna; Danziger-Isakov, Lara; Yen-Lieberman, Belinda et al. (2014) Multicenter comparison of laboratory performance in cytomegalovirus and Epstein-Barr virus viral load testing using international standards. Clin Transplant 28:1416-23
Batal, Ibrahim; De Serres, Sacha A; Mfarrej, Bechara G et al. (2014) Glomerular inflammation correlates with endothelial injury and with IL-6 and IL-1? secretion in the peripheral blood. Transplantation 97:1034-42
Reed, E F; Rao, P; Zhang, Z et al. (2013) Comprehensive assessment and standardization of solid phase multiplex-bead arrays for the detection of antibodies to HLA. Am J Transplant 13:1859-70
Daly, Kevin P; Seifert, Michael E; Chandraker, Anil et al. (2013) VEGF-C, VEGF-A and related angiogenesis factors as biomarkers of allograft vasculopathy in cardiac transplant recipients. J Heart Lung Transplant 32:120-8
Chandraker, Anil; Strom, Terry B (2013) Transplantation: a new molecular approach to the diagnosis of acute rejection. Nat Rev Nephrol 9:631-2

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