Apoptosis is a highly regulated program of cell death. Recent studies suggest that apoptosis is an important mechanism of tissue injury in allograft rejection. The hypothesis to be tested is that apoptosis has a dual role in the allograft, a deleterious role is a mechanism of graft cell damage and a beneficial role involving elimination of alloreactive cells. The overall goal of this project is to modulate apoptosis during organ transplantation so as to inhibit death of graft associated cells and to promote deletion of infiltrating host reactive cells. An integrated series of studies utilizing well defined animal models of orthotopic liver transplantation and small intestinal transplantation are proposed.
In Specific Aim 1 the mechanisms responsible for apoptotic graft damage during allograft rejection will be defined. RNase protection assays, and competitive reverse transcriptase polymerase chain reaction will be utilized to determine the cellular and soluble initiators as well as the signaling pathways which culminate in irreversible cell damage and death. Further studies will utilize functional assays to examine the proteolytic cleavage of caspases during graft rejection. Specific peptide inhibitors of caspase activation will be administered to allograft recipients to disrupt the apoptotic pathway and graft damage. The investigators have previously determined that CD8+ cells are not essential for allograft rejection or graft cell apoptosis. The apoptotic pathways that function independent of CD8 cells will therefore be elucidated and modulated in Specific Aim 2.
In Specific Aim 3 they will examine the role of apoptosis in inducing allograft tolerance. Recently, they have determined that depletion of the majority of host CD4+ T cells results in abundant apoptosis of graft infiltrating cells with minimal allograft damage and rejection. The cellular and biochemical mechanisms by which infiltrating lymphocytes are deleted will be examined using this model. Furthermore, the impact of conventional immunosuppressives and the deletion of alloreactive host lymphocytes will be studied. Definition and characterization of apoptotic pathways in organ transplantation will lead to novel therapeutics to enhance graft survival and eliminate alloreactive cells while preserving the host immune response.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Prasad, Shiv A
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Stanford University
Schools of Medicine
United States
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Krams, S M; Schaffert, S; Lau, A H et al. (2017) Applying Mass Cytometry to the Analysis of Lymphoid Populations in Transplantation. Am J Transplant 17:1992-1999
Vitalone, Matthew James; Wei, Liang; Fujiki, Masato et al. (2016) Liver microRNA Profile of Induced Allograft Tolerance. Transplantation 100:781-90
Hadad, Uzi; Martinez, Olivia; Krams, Sheri M (2014) NK cells after transplantation: friend or foe. Immunol Res 58:259-67
Wei, L; Wang, M; Qu, X et al. (2012) Differential expression of microRNAs during allograft rejection. Am J Transplant 12:1113-23
Pham, Betty; Piard-Ruster, Karine; Silva, Richard et al. (2012) Changes in natural killer cell subsets in pediatric liver transplant recipients. Pediatr Transplant 16:176-82
Wai, Lu-En; Garcia, Jordan A; Martinez, Olivia M et al. (2011) Distinct roles for the NK cell-activating receptors in mediating interactions with dendritic cells and tumor cells. J Immunol 186:222-9
Zhuo, Ming; Fujiki, Masato; Wang, Mouer et al. (2010) Identification of the rat NKG2D ligands, RAE1L and RRLT, and their role in allograft rejection. Eur J Immunol 40:1748-57
Fujiki, Masato; Esquivel, Carlos O; Martinez, Olivia M et al. (2010) Induced tolerance to rat liver allografts involves the apoptosis of intragraft T cells and the generation of CD4(+)CD25(+)FoxP3(+) T regulatory cells. Liver Transpl 16:147-54
Harris, A; Krams, S M; Martinez, O M (2010) MicroRNAs as immune regulators: implications for transplantation. Am J Transplant 10:713-9
Wai, Lu-En; Fujiki, Masato; Takeda, Saori et al. (2008) Rapamycin, but not cyclosporine or FK506, alters natural killer cell function. Transplantation 85:145-9

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