Heart/kidney co-transplantation in miniature swine provides the only consistent and reproducible model of nonablative cardiac allograft tolerance in large animals. It also mimics the beneficial effects of co-transplanting hearts and kidneys in humans. The mechanism by which a heart is protected from both acute and chronic rejection by the tolerant state induced by a kidney allograft is unknown. In our previous grant we characterized the role of the donor kidney and host thymus in tolerant heart/kidney recipients and began to investigate kidney-derived cell populations. Based on those studies, we now hypothesize that host thymus-derived regulatory T cells, generated by cells or antigens derived from the donor kidney, are responsible for the induction of tolerance to cardiac allografts in heart/kidney recipients. The corollary is that regulatory T cells are present in tolerant recipients bearing long-term cardiac allografts but are not present in chronically immunosuppressed recipients bearing long-term cardiac allografts. We will test this hypothesis by 1) determining the in vitro characteristics of regulatory T cells from tolerant heart/kidney recipients, 2) determining the role of regulatory T cells in the induction and maintenance phase of tolerance in heart/kidney recipients, 3) determining how a state of tolerance modifies the effects of intragraft cytokine excess in heart/kidney recipients, and 4) comparing the in vitro parameters of transplant immunity in animals bearing allogeneic heart transplants prolonged by tolerance induction vs. chronic immunosuppression. Understanding the mechanisms of T cell regulation may lead to novel tolerance strategies in human transplantation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL018646-26A1
Application #
6782110
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
2003-09-30
Project End
2008-08-31
Budget Start
2003-09-30
Budget End
2004-08-31
Support Year
26
Fiscal Year
2003
Total Cost
$493,034
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Smith, R N; Adam, B A; Rosales, I A et al. (2018) RNA expression profiling of renal allografts in a nonhuman primate identifies variation in NK and endothelial gene expression. Am J Transplant 18:1340-1350
Chatterjee, Debanjana; Moore, Carolina; Gao, Baoshan et al. (2018) Prevalence of polyreactive innate clones among graft--infiltrating B cells in human cardiac allograft vasculopathy. J Heart Lung Transplant 37:385-393
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

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