Our central hypothesis is that induction of robust, reproducible and durable, tolerance to cardiac allografts will 1) result in long-term graft survival, 2) preserve normal graft function, and 3) prevent cardiac allograft vasculopathy (CAV) without long term immunosuppression. Recent studies have demonstrated that the cotransplantation of vascularized donor thymus induces rapid and stable tolerance to MHC disparate hearts in miniature swine. The goal of this Project is to extrapolate this innovative strategy to nonhuman primates. However, preliminary attempts to co-transplant vascularized thymus and heart allografts in nonhuman primates resulted in early loss of the donor thymus followed by rejection of the heart. To explain this discrepancy, we hypothesize that nonhuman primate thymus grafts are more susceptible to early immune injury and inflammation than the porcine thymus grafts and that this early damage prevents cynomolgus thymus grafts from contributing fully to the induction of tolerance. We further hypothesize that the three most likely causes of early thymus injury in cynomolgus recipients are: 1) the early depletion of salutary host Tregs by high-dose ATG therapy, 2) the homeostatic expansion of deleterious memory T ceils by high-dose ATG therapy, and 3) the inflammation associated with the surgical procedure Our goal is develop an innovative and integrated strategy to block each of these events, preserve early thymic function and allow the transplanted thymus to participate fully in the induction of tolerance to cotransplanted cardiac allografts.
Our aims are 1) determine whether expanding host regulatory T cells in vivo will abrogate early thymic loss, 2) determine whether depleting or inhibiting memory T cells will prevent early thymic rejection, and 3) determine if dampening the pro-inflammatory response will diminish early thymus injury and promote tolerance in heart en bloc thymus allograft recipients.

Public Health Relevance

Heart transplant recipients do not survive long enough because the drugs used to prevent the immune system from attacking the organs are not completely effective and they make transplant recipients more susceptible to infections and cancer. We will find new ways to transplant organs without drugs using tolerance which makes the organs immunologically invisible to the recipient.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI094374-04
Application #
8523178
Study Section
Special Emphasis Panel (ZAI1-BDP-I)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
4
Fiscal Year
2013
Total Cost
$616,346
Indirect Cost
$167,631
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Wang, Zhaohui; Pratts, Shannon G; Zhang, Huiping et al. (2016) Treg depletion in non-human primates using a novel diphtheria toxin-based anti-human CCR4 immunotoxin. Mol Oncol 10:553-65
Hotta, Kiyohiko; Aoyama, Akihiro; Oura, Tetsu et al. (2016) Induced regulatory T cells in allograft tolerance via transient mixed chimerism. JCI Insight 1:
Aoyama, A; Tonsho, M; Ng, C Y et al. (2015) Long-term lung transplantation in nonhuman primates. Am J Transplant 15:1415-20
Tonsho, M; Lee, S; Aoyama, A et al. (2015) Tolerance of Lung Allografts Achieved in Nonhuman Primates via Mixed Hematopoietic Chimerism. Am J Transplant 15:2231-9
Madariaga, Maria Lucia L; Kreisel, Daniel; Madsen, Joren C (2015) Organ-specific differences in achieving tolerance. Curr Opin Organ Transplant 20:392-9
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
La Muraglia 2nd, G M; O'Neil, M J; Madariaga, M L et al. (2015) A novel approach to measuring cell-mediated lympholysis using quantitative flow and imaging cytometry. J Immunol Methods 427:85-93
Matthews, Kristin A; Tonsho, Makoto; Madsen, Joren C (2015) New-Onset Diabetes Mellitus After Transplantation in a Cynomolgus Macaque (Macaca fasicularis). Comp Med 65:352-6
Tonsho, Makoto; Michel, Sebastian; Ahmed, Zain et al. (2014) Heart transplantation: challenges facing the field. Cold Spring Harb Perspect Med 4:
Madariaga, M L; Michel, S G; Tasaki, M et al. (2013) Induction of cardiac allograft tolerance across a full MHC barrier in miniature swine by donor kidney cotransplantation. Am J Transplant 13:2558-66

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