Tolerance is induced in 100% of miniature swine recipients of renal allografts selectively mismatched for class I and treated with a 12 day course of Cyclosporine A perioperatively. Heart transplants across the same MHC barrier are prolonged significantly by the same treatment regimen, but all grafts are eventually rejected. We have therefore examined the response to simultaneous transplantation of both heart and kidney across this class I mismatch and have made the exciting observation that the kidney transplants appear to provide complete protection of the hears from both acute and chronic rejection. Our goal in the current proposal is to determine the basis of this protective phenomenon. Specifically, we shall: 1) Determine whether class I mismatched heart transplants are capable of maintaining the tolerance established by simultaneous transplantation of kidney and heart; 2) Determine the requirements for an intact thymus in the induction/maintenance of tolerance to class I mismatched heart transplants; 3) Examine which kidney-derived cell populations and/or antigens are responsible for induction of tolerance to class I mismatched heart transplants, and attempt to utilize such cells and/or antigens in lace of the kidney for tolerance induction; and 4) Compare in vitro parameters of transplant immunity/tolerance in animals bearing allogeneic heart transplants prolonged by tolerance induction versus Chronic immunosuppression. These studies should have both theoretical implications for our understanding of tolerance induction by primarily vascularized allografts and practical implications with respect to the application of tolerance-inducing regimens to heart transplantation.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts General Hospital
United States
Zip Code
Gonzalez-Nolasco, Bruno; Wang, Mengchuan; Prunevieille, Aurore et al. (2018) Emerging role of exosomes in allorecognition and allograft rejection. Curr Opin Organ Transplant 23:22-27
Smith, R N; Matsunami, M; Adam, B A et al. (2018) RNA expression profiling of nonhuman primate renal allograft rejection identifies tolerance. Am J Transplant 18:1328-1339
Fan, Martin Y; Low, Jun Siong; Tanimine, Naoki et al. (2018) Differential Roles of IL-2 Signaling in Developing versus Mature Tregs. Cell Rep 25:1204-1213.e4
Benichou, Gilles; Prunevieille, Aurore (2018) Graft-derived exosomes. When small vesicles play a big role in transplant rejection. Am J Transplant 18:1585-1586
Marangoni, Francesco; Zhang, Ruan; Mani, Vinidhra et al. (2018) Tumor Tolerance-Promoting Function of Regulatory T Cells Is Optimized by CD28, but Strictly Dependent on Calcineurin. J Immunol 200:3647-3661
Fan, Martin Y; Turka, Laurence A (2018) Immunometabolism and PI(3)K Signaling As a Link between IL-2, Foxp3 Expression, and Suppressor Function in Regulatory T Cells. Front Immunol 9:69
Wang, Zhaohui; Louras, Nathan J; Lellouch, Alexandre G et al. (2018) Dosing optimization of CCR4 immunotoxin for improved depletion of CCR4+ Treg in nonhuman primates. Mol Oncol 12:1374-1382
Newton, Ryan H; Shrestha, Sharad; Sullivan, Jenna M et al. (2018) Maintenance of CD4 T cell fitness through regulation of Foxo1. Nat Immunol 19:838-848
Hotta, Kiyohiko; Oura, Tetsu; Dehnadi, Abbas et al. (2018) Long-term Nonhuman Primate Renal Allograft Survival Without Ongoing Immunosuppression in Recipients of Delayed Donor Bone Marrow Transplantation. Transplantation 102:e128-e136
Robinson, Kortney A; Orent, William; Madsen, Joren C et al. (2018) Maintaining T cell tolerance of alloantigens: Lessons from animal studies. Am J Transplant 18:1843-1856

Showing the most recent 10 out of 305 publications