IFN-gamma and Fas/FasL pathways cooperate to induce medial cell loss and neointimal lesion formation in allograft vasculopathy.
Using a clinically relevant, fully disparate, allogeneic aortic transplant mouse model of allograft vasculopathy, we have demonstrated that neointimal proliferation is dependent on CD8(+) T cell effector pathways in the presence of therapeutic doses of calcineurin inhibitor (CNI) immunosuppression. CD4(+) T cell pathways are ablated by CNI immunosuppression. In the current study, we examined the relationship between CD8(+) T cell activities, medial SMC loss and neointimal hyperplasia. We demonstrate that at 5-6wk post transplantation in a wild type/wild type transplant CD8(+) T cell infiltration, CD8(+) CTL effector cell mediator expression and medial SMC loss all occur within aortic interposition grafts in the face of CNI immunosuppression. Both IFN-gamma and CTL mediated effector function is required for SMC loss and lesion formation under these conditions. Using strain combinations and reconstitution models, we provide data that blockade of the perforin/granzyme pathway does not prevent lesion formation but that blockade of the Fas/FasL pathway of cytotoxicity dramatically reduces SMC loss and prevents neointimal lesion formation. Both of these blockade strategies are in the face of an active IFN-gamma pathway. These data suggest a cooperative role between Fas/FasL and IFN-gamma mediated effector functions in medial SMC loss and neointimal lesion formation.
Hart-Matyas
Michael
M
Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4H7.
Nejat
Sara
S
Jordan
Julie L
JL
Hirsch
Gregory M
GM
Lee
Timothy D G
TD
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019703:Calcineurin / Q000008:administration & dosage; D002465:Cell Movement; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D053222:Fas Ligand Protein / Q000378:metabolism*; D006083:Graft Occlusion, Vascular / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007165:Immunosuppression Therapy; D007371:Interferon-gamma / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D008211:Lymphocyte Cooperation; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000473:pathology; D010750:Phosphoproteins / Q000008:administration & dosage; D017539:Tunica Intima / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D017540:Tunica Media / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019014:fas Receptor / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C113151:Cabin1 protein, mouse; D053222:Fas Ligand Protein; C491899:Fas protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D019014:fas Receptor; D007371:Interferon-gamma; D019703:Calcineurin