Our central hypothesis is that induction of robust, reproducible and durable, tolerance to cardiac allograftswill 1) result in long-term graft sun/ival, 2) preserve normal graft function, and 3) prevent cardiac allograftvasculopathy (CAV) without long term immunosuppression. Recent studies have demonstrated that thecotrahsplantation of vascularized donor thymus induces rapid and stable tolerance to MHC disparate heartsin 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 nonhumanprimates resulted in early loss of the donor thymus followed by rejection of the heart. To explain this screpancy, we hypothesize that nonhuman primate thymus grafts are more susceptible to earlyimmune injury and inflammation than the porcine thymus grafts and that this early damage preventscyiniomolgus thymus grafts from contributing fully to the induction of tolerance. We furtherhypothesize that the three most likely causes of early thymus injury in cynomolgus recipients are: 1) the earlydepletion of salutary host Tregs by high-dose ATG therapy, 2) the homeostatic expansion of deleteriousmemory T ceils by high-dose ATG therapy, and 3) the inflammation associated with the surgical procedureOur goal is develop an innovative and integrated strategy to block each of these events, preserve earlythymic function and allow the transplanted thymus to participate fully in the induction of tolerance tocotransplanted cardiac allografts.
Our aims are 1) determine whether expanding host regulatory T cells invivo will abrogate early thymic loss, 2) determine whether depleting or inhibiting memory T cells will preventearly thymic rejection, and 3) determine if dampening the pro-inflammatory response will diminish earlythymus 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 immunesystem from attacking the organs are not completely effective and they make transplant recipients moresusceptible to infections and cancer. We will find new ways to transplant organs without drugs usingtolerance 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 #
5U01AI094374-02
Application #
8130719
Study Section
Special Emphasis Panel (ZAI1-BDP-I (M2))
Program Officer
Kraemer, Kristy A
Project Start
2010-09-01
Project End
2015-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
2
Fiscal Year
2011
Total Cost
$857,225
Indirect Cost
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

Showing the most recent 10 out of 30 publications