title: Early T cell response to allografts occurring prior to alloantigen priming up-regulates innate-mediated inflammation and graft necrosis.
abstract: The early inflammatory response within organ allografts is initiated by ischemia/reperfusion (I/R) and promotes subsequent alloantigen-primed T cell recruitment into and rejection of the graft. Polymorphonuclear leukocyte (PMN)-mediated tissue damage is a primary component of the early inflammation in allograft rejection. We sought to compare and elucidate the mechanism of early PMN infiltration into cardiac isografts and allografts. Despite identical production of PMN attractant chemokines, PMN infiltration following reperfusion into syngeneic and allogeneic grafts was not equivalent. PMN infiltration into isografts peaked at 9 to 12 hours post-transplant and quickly resolved. In contrast, PMN infiltration into allografts continued to elevated levels, peaking at 24 hours post-reperfusion. This amplified PMN infiltration into allografts did not resolve until 72 hours post-reperfusion and was accompanied by marked parenchymal necrosis. This early innate inflammatory response was regulated by IFN-gamma-producing CD8+ T cells present in the recipient before detectable alloantigen T cell priming. Co-culture with CD62L(low) CD8+ T cells, but not CD62L(high) CD8+ or CD62L(low) CD4+ T cells, harvested from naïve animals induced allogeneic endothelial cells to express IFN-gamma-dependent chemokines. These data demonstrate CD8+ T cell-mediated attack on the vascular endothelium of allografts within hours following organ reperfusion that amplifies innate immune-mediated intra-graft inflammation and necrosis.
authors.affiliation: Department of Immunology, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. tarek@crwu.edu
authors.forename: Tarek
authors.initials: T
authors.lastname: El-Sawy
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Miura
authors.forename: Robert
authors.initials: R
authors.lastname: Fairchild
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral; D018925:Chemokines / Q000378:metabolism; D018920:Coculture Techniques; D004730:Endothelium, Vascular / Q000166:cytology; D004797:Enzyme-Linked Immunosorbent Assay; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology*; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D007249:Inflammation / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology; D007519:Isoantigens / Q000276:immunology*; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000276:immunology*; D013997:Time Factors; D014184:Transplantation, Homologous; D015854:Up-Regulation
chemical_list: D018925:Chemokines; D007519:Isoantigens; D007371:Interferon-gamma