Impairment of recipient cytolytic activity attenuates allograft vasculopathy.
We investigated the role of CD4+ and CD8+ T subsets as well as T cell cytolytic effector mechanisms in the aortic allograft model of allograft vasculopathy using CD4 and CD8 gene knockout mice (CD4(-/-), CD8(-/-)) and mice deficient in cytolytic effector pathways. Medial apoptosis at 2 weeks was reduced in CD8(-/-) mice and in mice where cytotoxic T cell activity was compromised. At 8 weeks, substantial medial damage was observed in wild-type (WT) and CD4(-/-) recipients but medial preservation was evident in CD8(-/-) mice and in mice with impaired cytotoxic T cell activity. The intima/media ratio, a comprehensive measure of allograft vasculopathy, was similar in WT and CD4(-/-) recipients but was significantly reduced in CD8(-/-) mice and mice with impaired cytotoxic T cell activity. These data indicate that CD8+ T cells contribute to the vascular remodeling that is characteristic of allograft vasculopathy. They also show that CD8+ T cells participate in allograft vasculopathy in the absence of CD4+ T cell help. We further demonstrated that WT mice exhibited robust allograft vasculopathy in the presence of cyclosporin A immunosuppression but that allograft vasculopathy was ablated in cyclosporin-treated CD8(-/-) mice. This supports the hypothesis that non-CD8+ T cell effector mechanisms are sensitive to calcineurin inhibitor therapy but that CD8+ T cell-mediated allograft vasculopathy is refractory to such treatment. Taken together, our data suggest that CD8+ T cells contribute to the induction of vascular remodeling in allograft vasculopathy and provide evidence that novel therapies which target CD8+ T cell effector function might be effective in mitigating AV in the clinical setting.
Skaro
Anton I
AI
Department of Surgery, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4H7.
Liwski
Robert S
RS
O'Neill
Jennifer
J
Vessie
Ellen L
EL
Zhou
Juan
J
Hirsch
Gregory M
GM
Lee
Timothy D G
TD
D000818:Animals; D001011:Aorta / Q000637:transplantation*; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000473:pathology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014184:Transplantation, Homologous