Acute rejection remains a significant problem in clinical transplantation, undermining the survival of organs transplanted for treatment of end-stage organ disease. Acute rejection is mediated by the coordinated infiltration and effector functions of alloantigen-specific T cells resulting in graft tissue destruction. Factors directing T cells and other leukocytes into allografts remain poorly defined. During the previous cycle of this grant we demonstrated the early (e.g. 9-24 hours post-transplant) infiltration of neutrophils into cardiac iso- and allo-grafts. However, neutrophil infiltration into allografts is increased 3-4 fold compared to isografts and is associated with detectable areas of parenchymal tissue necrosis indicating the ability of the recipient to react to the presence of allogeneic tissue as early as 12-24 hours post-transplant. Subsequent studies indicated that the increased neutrophil infiltration into allografts is mediated by CD8 T cells expressing a memory phenotype. Antagonism of early neutrophil infiltration into cardiac allografts decreases the efficiency of alloantigen-primed effector T cell infiltration into the allografts with a 10-15 day prolongation of allograft survival. When this antagonism is combined with a low dose of costimulatory blockade to delay donor-specific effector T cell activation, the cardiac allografts survive longer than 130 days with little-no cellular infiltration into the grafts. The studies proposed in this Continuation Renewal will test the hypothesis that initial neutrophil infiltration into cardiac iso- and allo-grafts is mediated by an organized and interdependent program of cytokine and chemokine production, that donor-reactive memory CD8 T cells amplify this early neutrophil infiltration into the allograft and induce neutrophil activation in the allograft, and that this neutrophil activation results in changes, or "marking", of the allograft tissue that promotes the recruitment of donor antigen-primed effector T cells into the allograft. This hypothesis will be tested in three Specific Aims: 1) To test the induction and role of early innate immune components that direct neutrophil infiltration into cardiac iso- and allo-grafts;2) To test the phenotype, specificity and function of CD8 T cells that amplify neutrophil infiltration and activation in allografts;and, 3) To test neutrophil activation functions that direct donor antigen-primed effector T cell infiltration into cardiac allografts. The results of these studies will elucidate poorly understood inflammatory events that occur almost immediately after reperfusion of cardiac allografts. Solid organ transplantation includes a period where the organ is removed from an oxygen supply and underlies an intense inflammatory response induced during revascularization of the organ. Although this inflammation enhances the recipient immune response to the graft and promotes rejection, the key components of this initial inflammation in the graft and their interaction with the recipient immune system are poorly understood. The results of the proposed studies will reveal novel cellular and molecular interactions that increase the intensity of early inflammation in transplanted organs and will provide novel targets to attenuate this inflammation and promote better function and survival of solid organs transplanted for the treatment of end-stage organ disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI040459-15
Application #
8197299
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Kehn, Patricia J
Project Start
1997-04-01
Project End
2012-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
15
Fiscal Year
2012
Total Cost
$378,564
Indirect Cost
$133,539
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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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
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
Su, C A; Iida, S; Abe, T et al. (2014) Endogenous memory CD8 T cells directly mediate cardiac allograft rejection. Am J Transplant 14:568-79
Traitanon, Opas; Poggio, Emilio D; Fairchild, Robert L (2014) Molecular monitoring of alloimmune-mediated injury in kidney transplant patients. Curr Opin Nephrol Hypertens 23:625-30
Su, Charles A; Fairchild, Robert L (2014) Memory T Cells in Transplantation. Curr Transplant Rep 1:137-146
Setoguchi, K; Hattori, Y; Iida, S et al. (2013) Endogenous memory CD8 T cells are activated within cardiac allografts without mediating rejection. Am J Transplant 13:2293-307
Baldwin 3rd, William M; Halushka, Marc K; Valujskikh, Anna et al. (2012) B cells in cardiac transplants: from clinical questions to experimental models. Semin Immunol 24:122-30
Fukuzawa, Nobuyuki; Petro, Marianne; Baldwin 3rd, William M et al. (2011) A TLR5 agonist inhibits acute renal ischemic failure. J Immunol 187:3831-9
Setoguchi, K; Schenk, A D; Ishii, D et al. (2011) LFA-1 antagonism inhibits early infiltration of endogenous memory CD8 T cells into cardiac allografts and donor-reactive T cell priming. Am J Transplant 11:923-35

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