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 #
5U01AI094374-03
Application #
8380343
Study Section
Special Emphasis Panel (ZAI1-BDP-I)
Project Start
Project End
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
3
Fiscal Year
2012
Total Cost
$614,587
Indirect Cost
$186,384
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Wang, Zhaohui; Zheng, Qian; Zhang, Huiping et al. (2017) Ontak-like human IL-2 fusion toxin. J Immunol Methods 448:51-58
Zheng, Qian; Wang, Zhaohui; Zhang, Huiping et al. (2017) Diphtheria toxin-based anti-human CD19 immunotoxin for targeting human CD19+ tumors. Mol Oncol 11:584-594
Purroy, Carolina; Fairchild, Robert L; Tanaka, Toshiaki et al. (2017) Erythropoietin Receptor-Mediated Molecular Crosstalk Promotes T Cell Immunoregulation and Transplant Survival. J Am Soc Nephrol 28:2377-2392
Hotta, Kiyohiko; Aoyama, Akihiro; Oura, Tetsu et al. (2016) Induced regulatory T cells in allograft tolerance via transient mixed chimerism. JCI Insight 1:
Wang, Zhaohui; Navarro-Alvarez, Nalu; Shah, Jigesh A et al. (2016) Porcine Treg depletion with a novel diphtheria toxin-based anti-human CCR4 immunotoxin. Vet Immunol Immunopathol 182:150-158
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
Nuñez, Sarah; Moore, Carolina; Gao, Baoshan et al. (2016) The human thymus perivascular space is a functional niche for viral-specific plasma cells. Sci Immunol 1:
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
Madariaga, Maria Lucia L; Kreisel, Daniel; Madsen, Joren C (2015) Organ-specific differences in achieving tolerance. Curr Opin Organ Transplant 20:392-9

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