Xenotransplantation remains the best near-term hope for alleviating the critical shortage of allogeneic organs. A major advance in organ xenograft survival has been the development of a knock-out strain of miniature swine (GalT-KO), which are not subject to the severe rejection previously caused by natural anti- Gal antibodies. Our initial studies using these animals as donors demonstrated a marked improvement in the survival of life-supporting renal transplants when recipient baboons were treated with a regimen designed to induce T cell tolerance, as compared to relying on chronic immunosuppression. During this project period, we have expanded our studies of tolerance induction across the pig-to-baboon barrier and have achieved specific loss of primate anti-pig reactivity in several protocols, supporting the feasibility of tolerance induction. Nevertheless, significant problems remain before xenotransplantation will be applicable clinically. This resubmission application combines four component projects that encompass the most pressing problems and the most promising approaches in this field of research: 1) tolerance induction through vascularized thymic transplantation;2) tolerance induction through mixed chimerism;3) modeling of tolerance in mice with human immune systems;and 4) thromboregulatory barriers to xenotransplantation. All of these projects are highly interactive, and utilize numerous shared resources, many of which will be made available through the large and small animal cores. The work will be carried out in a unique environment, which provides interactions among scientists working in basic and cellular immunology as well as with clinicians committed to taking new therapies to clinical applications.

Public Health Relevance

Xenotransplantation remains the best near-term hope for alleviating the critical shortage of allogeneic organs today. This Program Project grant combines four component projects that encompass what we consider to be the most pressing problems and the most promising approaches in this field of research.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI045897-13
Application #
8499187
Study Section
Special Emphasis Panel (ZAI1-QV-I (M2))
Program Officer
Nabavi, Nasrin N
Project Start
2001-09-01
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
13
Fiscal Year
2013
Total Cost
$2,761,778
Indirect Cost
$813,937
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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Tanabe, T; Watanabe, H; Shah, J A et al. (2017) Role of Intrinsic (Graft) Versus Extrinsic (Host) Factors in the Growth of Transplanted Organs Following Allogeneic and Xenogeneic Transplantation. Am J Transplant 17:1778-1790
Yamada, Kazuhiko; Sykes, Megan; Sachs, David H (2017) Tolerance in xenotransplantation. Curr Opin Organ Transplant 22:522-528
Mastroianni, Melissa; Ng, Zhi Yang; Goyal, Ritu et al. (2017) Topical Delivery of Immunosuppression to Prolong Xenogeneic and Allogeneic Split-Thickness Skin Graft Survival. J Burn Care Res :
Tan, Shulian; Li, Yang; Xia, Jinxing et al. (2017) Type 1 diabetes induction in humanized mice. Proc Natl Acad Sci U S A 114:10954-10959

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