Graft loss from chronic rejection, which affects all solid organs to varying degrees, has become the major obstacle to the long-term success of lung transplantation. We have established a large animal model of chronic lung rejection, which reproduces with fidelity and consistency, the pathological lesions seen in human lung transplant recipients suffering from chronic rejection. Based on preliminary data and human studies, we hypothesize that chronic lung rejection is an immunologically mediated process driven by T cell recognition of major and minor histocompatibility antigens. The corollary to this hypothesis is that protocols to downregulate the immune system or to induce immune tolerance will most effectively prevent, interrupt and/or reverse chronic lung rejection. The goal of this proposal is to test this hypothesis and, in doing so, investigate the immunologic mechanisms underlying the process of chronic lung rejection. Using MHC inbred miniature swine, synthetic polymorphic allopeptides, and monoclonal antibodies cross-reactive for swine T cells, we plan to (1) define the immunogenetic requirements of chronic lung allograft rejection and characterize the cellular and humoral mechanisms that mediate this disease, (2) examine the role and mechanisms of indirect allorecognition of donor MHC peptides in the development of chronic lung rejection in miniature swine, and (3) determine the role of costimulatory molecules in the pathogenesis of chronic lung rejection in miniature swine. These studies should lead to a better understanding of the cellular and molecular mechanisms of chronic lung rejection in a clinically relevant experimental model and may ultimately lead to the development of new strategies to prevent or treat this disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL067110-01A1
Application #
6437219
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Reynolds, Herbert Y
Project Start
2002-07-01
Project End
2006-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
1
Fiscal Year
2002
Total Cost
$329,155
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
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
Aoyama, A; Tonsho, M; Ng, C Y et al. (2015) Long-term lung transplantation in nonhuman primates. Am J Transplant 15:1415-20
Meltzer, A J; Veillette, G R; Aoyama, A et al. (2012) Donor brain death inhibits tolerance induction in miniature swine recipients of fully MHC-disparate pulmonary allografts. Am J Transplant 12:1290-5
Nguyen, Bao-Ngoc H; Azimzadeh, Agnes M; Schroeder, Carsten et al. (2011) Absence of Gal epitope prolongs survival of swine lungs in an ex vivo model of hyperacute rejection. Xenotransplantation 18:94-107
Ng, Choo Y; Madsen, Joren C; Rosengard, Bruce R et al. (2009) Immunosuppression for lung transplantation. Front Biosci (Landmark Ed) 14:1627-41
Weiss, Matthew J; Madsen, Joren C; Rosengard, Bruce R et al. (2008) Mechanisms of chronic rejection in cardiothoracic transplantation. Front Biosci 13:2980-8
Meltzer, Andrew J; Weiss, Matthew J; Veillette, Gregory R et al. (2008) Repetitive gastric aspiration leads to augmented indirect allorecognition after lung transplantation in miniature swine. Transplantation 86:1824-9
Nguyen, Bao-Ngoc H; Azimzadeh, Agnes M; Zhang, Tianshu et al. (2007) Life-supporting function of genetically modified swine lungs in baboons. J Thorac Cardiovasc Surg 133:1354-63
Shoji, Tsuyoshi; Sahara, Hisashi; Muniappan, Ashok et al. (2007) Operational tolerance to class I disparate lungs can be induced despite pretransplant immunization with class I allopeptides. Transplantation 84:1467-73
Sahara, H; Shoji, T; Ng, C Y et al. (2006) The role of indirect recognition of MHC class I and II allopeptides in a fully mismatched miniature swine model of lung transplantation. Transplant Proc 38:3256-8

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