IFN-γ and Fas/FasL pathways cooperate to induce medial cell loss and neointimal lesion formation in allograft vasculopathy

We demonstrate that at 5-6 wk 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-γ 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-γ pathway. These data suggest a cooperative role between Fas/FasL and IFN-γ mediated effector functions in medial SMC loss and neointimal lesion formation.