The acute rejection of allografts is mediated by alloantigen-specific T cells. Although the effector T cells are primed in the recipient lymphoid tissue, the factors directing the migration and infiltration of the primed T cells into the graft tissue remain unclear. An important parameter in facilitating leukocyte migration and infiltration into tissue is the presence of inflammation. Post-transplant inflammation, initially provoked by surgical trauma, is mediated through the production of proinflammatory cytokines and the induced expression of adhesion molecules on vascular endothelium. Recent results from this laboratory have indicated the amplified expression of genes encoding chemoattractant cytokines following transplantation of mice with allogeneic skin grafts when compared to the expression in control, syngeneic grafts. This amplified expression occurs prior to times post-transplant when primed alloantigen-specific T cells can be detected in the spleen or lymph nodes. On the basis of these results, we propose the hypothesis that the initial inflammatory response observed following transplantation is higher with increased immunogenetic disparity between the donor and recipient and that this amplified inflammatory response is mediated by innate cellular mechanisms following interaction of graft cells with infiltrating recipient cells. The experiments proposed in this application will test this hypothesis by determining the levels of inflammation in recipients transplanted with skin grafts of defined degrees of allogeneic difference, determining the sequential appearance of proinflammatory cytokine production during this initial inflammatory response, determining the interdependence of proinflammatory cytokine production, and determining the donor and recipient cellular components mediating the amplified inflammatory response following allogeneic skin transplantation. The results of these studies will address critical issues in the initiation of inflammation following transplantation of allogeneic grafts which facilitates the infiltration of effector T cells. The results should provide novel information, useful in the design or strategies to suppress or neutralize this initial inflammatory response and prolong the function and the survival of transplanted allografts.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI040459-03
Application #
2887321
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Kerr, Lawrence D
Project Start
1997-04-01
Project End
2002-03-31
Budget Start
1999-04-01
Budget End
2000-03-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Type
DUNS #
017730458
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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Iida, Shoichi; Miyairi, Satoshi; Su, Charles A et al. (2018) Peritransplant VLA-4 blockade inhibits endogenous memory CD8 T cell infiltration into high-risk cardiac allografts and CTLA-4Ig resistant rejection. Am J Transplant :
Tsuda, Hidetoshi; Su, Charles A; Tanaka, Toshiaki et al. (2018) Allograft dendritic cell p40 homodimers activate donor-reactive memory CD8+ T cells. JCI Insight 3:
Ayasoufi, Katayoun; Kohei, Naoki; Nicosia, Michael et al. (2018) Aquaporin 4 blockade improves survival of murine heart allografts subjected to prolonged cold ischemia. Am J Transplant 18:1238-1246
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Iida, Shoichi; Tsuda, Hidetoshi; Tanaka, Toshiaki et al. (2016) IL-1 Receptor Signaling on Graft Parenchymal Cells Regulates Memory and De Novo Donor-Reactive CD8 T Cell Responses to Cardiac Allografts. J Immunol 196:2827-37
Abe, T; Su, C A; Iida, S et al. (2014) Graft-derived CCL2 increases graft injury during antibody-mediated rejection of cardiac allografts. Am J Transplant 14:1753-64
Traitanon, O; Gorbachev, A; Bechtel, J J et al. (2014) IL-15 induces alloreactive CD28(-) memory CD8 T cell proliferation and CTLA4-Ig resistant memory CD8 T cell activation. Am J Transplant 14:1277-89
Ishii, Daisuke; Rosenblum, Joshua M; Nozaki, Taiji et al. (2014) Novel CD8 T cell alloreactivities in CCR5-deficient recipients of class II MHC disparate kidney grafts. J Immunol 193:3816-24
Su, Charles A; Fairchild, Robert L (2014) Memory T Cells in Transplantation. Curr Transplant Rep 1:137-146

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