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 #
5P01AI045897-12
Application #
8299011
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
2012-07-01
Budget End
2013-06-30
Support Year
12
Fiscal Year
2012
Total Cost
$2,968,972
Indirect Cost
$877,116
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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Yamada, Kazuhiko; Tasaki, Masayuki; Sekijima, Mitsuhiro et al. (2014) Porcine cytomegalovirus infection is associated with early rejection of kidney grafts in a pig to baboon xenotransplantation model. Transplantation 98:411-8
Wang, Yuantao; Wang, Hui; Bronson, Roderick et al. (2014) Rapid dendritic cell activation and resistance to allotolerance induction in anti-CD154-treated mice receiving CD47-deficient donor-specific transfusion. Cell Transplant 23:355-63
Navarro-Alvarez, Nalu; Yang, Yong-Guang (2014) Lack of CD47 on donor hepatocytes promotes innate immune cell activation and graft loss: a potential barrier to hepatocyte xenotransplantation. Cell Transplant 23:345-54
Kalscheuer, Hannes; Onoe, Takashi; Dahmani, Alexander et al. (2014) Xenograft tolerance and immune function of human T cells developing in pig thymus xenografts. J Immunol 192:3442-50
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Tena, A; Kurtz, J; Leonard, D A et al. (2014) Transgenic expression of human CD47 markedly increases engraftment in a murine model of pig-to-human hematopoietic cell transplantation. Am J Transplant 14:2713-22
Scalea, Joseph R; Villani, Vincenzo; Gillon, Bradford C et al. (2014) Development of antidonor antibody directed toward non-major histocompatibility complex antigens in tolerant animals. Transplantation 98:514-9
Sekijima, Mitsuhiro; Waki, Shiori; Sahara, Hisashi et al. (2014) Results of life-supporting galactosyltransferase knockout kidneys in cynomolgus monkeys using two different sources of galactosyltransferase knockout Swine. Transplantation 98:419-26
Haspot, F; Li, H W; Lucas, C L et al. (2014) Allospecific rejection of MHC class I-deficient bone marrow by CD8 T cells. Am J Transplant 14:49-58

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