? This proposal details a five year training program for the applicant's transition from research investigator to independent investigator. The principal investigator has completed doctoral training in molecular immunology and post-doctoral training in molecular embryology, and now continues his training in transplant immunology. ? The present training emphasizes mechanisms of transplantation tolerance. James Markmann MD, PhD will mentor the scientific development of the principal investigator. Dr Markmann is a recognized leader in the field of transplantation research. He has trained numerous young scientists including research fellows and graduate students. An advisory committee of three well-recognized scientists from the institution's basic immunology community will provide necessary scientific and professional guidance. The Department of Surgery at the University of Pennsylvania provides an excellent environment for training research investigators and has a long history of transitioning them into independent investigators. The environment combines basic exploratory research as well as direct clinical applications for discovery. ? The research focuses on capitalizing on the unique properties of regulatory T cells (Tregs) to generate allograft tolerance. Specifically, our thesis is that rendering Tregs nonfunctional by inflammatory signals is a standard mechanism by which the immune system promotes initiation of an immune response. We base this on preliminary data suggesting that in the setting of allogeneic organ transplantation, innate inflammatory signals accompanying the procedure of organ transplantation interfere with the function of Tregs by triggering of the glucocorticoid-induced TNFR family-related gene (GITR) by its ligand (GITRL). Moreover, our preliminary data demonstrate that blockade of GITR triggering results in long-term skin allograft survival that is Treg-dependent. Thus we propose to delineate the mechanisms underlying the beneficial impact of GITR blockade on transplantation tolerance and to evaluate whether targeting this receptor-ligand pair can be exploited for therapeutic benefit in standard transplant tolerance models. First, we will assess the scope of the benefit derived from targeting GITR-GITRL employing a panel of transplantation tolerance models. Second, we will characterize the immunological mechanisms, cellular and molecular, by which Treg suppressor activity is augmented through disruption of GITR-GITRL interaction in vivo. ? A state of transplantation tolerance without the need for maintenance immunosuppressive therapy remains an elusive goal for immunobiologists. Our research focuses a novel and potentially clinically relevant approach to this end. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01DK079207-02
Application #
7475154
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Hyde, James F
Project Start
2007-08-01
Project End
2010-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
2
Fiscal Year
2008
Total Cost
$137,160
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Lee, Kang Mi; Yeh, Heidi; Zhao, Gaoping et al. (2014) B-cell depletion improves islet allograft survival with anti-CD45RB. Cell Transplant 23:51-8
Lee, K M; Kim, J I; Stott, R et al. (2012) Anti-CD45RB/anti-TIM-1-induced tolerance requires regulatory B cells. Am J Transplant 12:2072-8
Kim, James I; O'connor, Matthew R; Duff, Patrick E et al. (2011) Generation of adaptive regulatory T cells by alloantigen is required for some but not all transplant tolerance protocols. Transplantation 91:707-13
Zhao, Gaoping; Moore, Daniel J; Kim, James I et al. (2011) Inhibition of transplantation tolerance by immune senescence is reversed by endocrine modulation. Sci Transl Med 3:87ra52
Kim, James I; Sonawane, Samsher B; Lee, Major K et al. (2010) Blockade of GITR-GITRL interaction maintains Treg function to prolong allograft survival. Eur J Immunol 40:1369-74
Zhao, G; Moore, D J; Lee, K M et al. (2010) An unexpected counter-regulatory role of IL-10 in B-lymphocyte-mediated transplantation tolerance. Am J Transplant 10:796-801
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
Kim, J I; Lee 4th, M K; Moore, D J et al. (2009) Regulatory T-cell counter-regulation by innate immunity is a barrier to transplantation tolerance. Am J Transplant 9:2736-44
Sonawane, Samsher B; Kim, James I; Lee, Major K et al. (2009) GITR Blockade Facilitates Treg Mediated Allograft Survival. Transplantation 88:1169-77
Huang, Xiaolun; Moore, Daniel J; Mohiuddin, Mohammad et al. (2008) Inhibition of ICAM-1/LFA-1 interactions prevents B-cell-dependent anti-CD45RB-induced transplantation tolerance. Transplantation 85:675-80