Our laboratory has recently shown that while cardiac allograft vasculopathy (CAV) requires histoincompatibility to develop, it can occur in tolerant recipients and even in immunodeficient recipients devoid of any adaptive immune response. Thus, additional mechanisms beyond conventional immune responsiveness on the part of the recipient to donor antigens appear to be present. We hypothesize that components of the innate immune system, particularly NK cells, contribute to the pathogenesis of CAV. This would represent a previously unidentified pathway toward CAV that might not be targeted by current chronic immunosuppressive therapy. To our knowledge a systematic and controlled study of the contribution of innate immunity to CAV has not been performed. In our first aim, we plan to fully characterize the role of NK cells and macrophages in the biological!y simple setting of parental to F1 transplants, and in combinations involving nonreactive (RAG1 -/-) mice incorporating vitro assays of NK cell function. In a second aim, we plan to investigate the most likely mechanisms further, including the involvement of IFN-gamma, perforin, and the fractalkine system. In a third aim we will explore in chimeric, tolerant recipients the importance of the factors established in Aims 1 and 2. In a fourth aim we will take these observations further by examining the efficacy of eliminating innate immune components from normal recipients undergoing various forms of immunosuppression of clinical relevance. This will afford an opportunity to evaluate the importance of innate reactivity as a causative component in a clinically relevant setting.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL071932-04
Application #
7092511
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Massicot-Fisher, Judith
Project Start
2003-09-10
Project End
2009-07-31
Budget Start
2006-08-01
Budget End
2009-07-31
Support Year
4
Fiscal Year
2006
Total Cost
$380,103
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Hirohashi, Tsutomu; Chase, Catharine M; DellaPelle, Patricia et al. (2014) Depletion of T regulatory cells promotes natural killer cell-mediated cardiac allograft vasculopathy. Transplantation 98:828-34
Shinoda, K; Akiyoshi, T; Chase, C M et al. (2014) Depletion of foxp3(+) T cells abrogates tolerance of skin and heart allografts in murine mixed chimeras without the loss of mixed chimerism. Am J Transplant 14:2263-2274
Hirohashi, T; Chase, C M; Della Pelle, P et al. (2012) A novel pathway of chronic allograft rejection mediated by NK cells and alloantibody. Am J Transplant 12:313-21
Russell, Paul S; Chase, Catharine M; Madsen, Joren C et al. (2011) Coronary artery disease from isolated non-H2-determined incompatibilities in transplanted mouse hearts. Transplantation 91:847-52
Miyajima, Masahiro; Chase, Catharine M; Alessandrini, Alessandro et al. (2011) Early acceptance of renal allografts in mice is dependent on foxp3(+) cells. Am J Pathol 178:1635-45
Hirohashi, T; Uehara, S; Chase, C M et al. (2010) Complement independent antibody-mediated endarteritis and transplant arteriopathy in mice. Am J Transplant 10:510-7
Graham, Jay A; Fray, Michael; de Haseth, Stephanie et al. (2010) Suppressive regulatory T cell activity is potentiated by glycogen synthase kinase 3{beta} inhibition. J Biol Chem 285:32852-9
Graham, J A; Wilkinson, R A; Hirohashi, T et al. (2009) Viral infection induces de novo lesions of coronary allograft vasculopathy through a natural killer cell-dependent pathway. Am J Transplant 9:2479-84
Ng, Choo Y; Madsen, Joren C; Rosengard, Bruce R et al. (2009) Immunosuppression for lung transplantation. Front Biosci (Landmark Ed) 14:1627-41
Millington, Timothy M; Madsen, Joren C (2009) Innate immunity in heart transplantation. Curr Opin Organ Transplant 14:571-6

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