Despite improvements in early post-transplant survival rates over the last two decades, a relentless annualattrition of 3-5% in recipients of previously functioning organ allografts continues to limit longer term outcomes. Success rates following pancreatic islet transplantation are even less acceptable. The major objectives of this multi-project research Program are to improve the long-term outcome following kidney and kidney/islet transplantation for both living and deceased donor transplants. We intend to investigate, in clinically relevant NHP models 1) the conditions necessary for consistent induction of durable allograft tolerance for both living and deceased donor transplants;2) the genetic and technical parameters required for successful composite IK transplants from living donors;and 3) the immunological mechanisms involved in tolerance of kidney, islet, and islet-kidney (IK) allografts. Clinical translation of therapeutic protocols for reliably achieving donor-specific immunologic non-responsiveness would eliminate much of the currently observed annual attrition of transplanted organs and tissues as well as the morbidities associated with the administration of lifelong immunosuppressive agents. We have previously shown that allograft tolerance can be induced in NHP via several approaches, one of which (mixed chimerism) we have extended to humans. In those seminal trials, long-term (2-8yrs) immunosuppression-free, stable renal function has been achieved in 7/10 initial recipients of HLA mismatched live-donor renal allografts selected for study. Although this achievement is dramatic, it is currently reliant upon conditioning, the application of which is limited to living donor recipients (beginning 6 days pre-transplant) and to a "tolerogenic" organ (kidney). The main hypotheses to be pursued in this Program are: 1) that reproducible induction of more robust and durable chimerism or cotransplantation of the kidney with islets will extend the application of this means of tolerance induction to a much wider population of allograft recipients, including those of deceased-donor kidneys and of islets, and, 2) that the current protocol can be effectively extended to islets from a living donor if the islet are included as part of a composite IK allograft. The studies planned will clarify the mechanisms involved with tolerance induction via the mixed chimerism approach and define the parameters that will allow rapid translation of these clinically relevant observations to treatment of diabeti patients who are candidates for kidney/pancreas transplantation.

Public Health Relevance

The major objectives of this multi-project research Program are to improve the long-term outcome following kidney and islet transplantation through research in clinically relevant NHP models. We will investigate novel approaches for induction of immunologic tolerance in recipients of both living and deceased donor transplants. Such tolerance would eliminate much of the current chronic loss of transplants as well as the morbidities caused by immunosuppressive drugs.

Agency
National Institute of Health (NIH)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI102405-03
Application #
8686741
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Kraemer, Kristy A
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
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Oura, Tetsu; Ko, Dicken S C; Boskovic, Svjetlan et al. (2016) Kidney Versus Islet Allograft Survival After Induction of Mixed Chimerism With Combined Donor Bone Marrow Transplantation. Cell Transplant 25:1331-41
Hotta, Kiyohiko; Aoyama, Akihiro; Oura, Tetsu et al. (2016) Induced regulatory T cells in allograft tolerance via transient mixed chimerism. JCI Insight 1:
Kant, Cavit D; Akiyama, Yoshinobu; Tanaka, Katsunori et al. (2015) Both rejection and tolerance of allografts can occur in the absence of secondary lymphoid tissues. J Immunol 194:1364-71
Wang, Ping; Schuetz, Christian; Vallabhajosyula, Prashanth et al. (2015) Monitoring of Allogeneic Islet Grafts in Nonhuman Primates Using MRI. Transplantation 99:1574-81
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Oura, Tetsu; Hotta, Kiyohiko; Cosimi, A B et al. (2015) Transient mixed chimerism for allograft tolerance. Chimerism 6:21-6
Yamada, Y; Nadazdin, O; Boskovic, S et al. (2015) Repeated Injections of IL-2 Break Renal Allograft Tolerance Induced via Mixed Hematopoietic Chimerism in Monkeys. Am J Transplant 15:3055-66
Granados, Jose M M; Benichou, Gilles; Kawai, Tatsuo (2015) Hematopoietic stem cell infusion/transplantation for induction of allograft tolerance. Curr Opin Organ Transplant 20:49-56
Scalea, Joseph R; Villani, Vincenzo; Gillon, Bradford C et al. (2014) Development of antidonor antibody directed toward non-major histocompatibility complex antigens in tolerant animals. Transplantation 98:514-9

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