CD8(+) T cells mediate aortic allograft vasculopathy under conditions of calcineurin immunosuppression: role of IFN-gamma and CTL mediators.
We have developed a model of aortic allograft vasculopathy (AV) that uses mouse strains that are fully disparate at Class I, Class II and minor histocompatibility antigens. Acute rejection is ablated with therapeutic doses of the calcineurin inhibitor Cyclosporine A (CyA). In this way we successfully mimic human disease. Using this model we have demonstrated, with cell transfer models using highly purified T cell populations, that calcineurin inhibitors ablate CD4(+) T cell effector mechanisms. As such, in the presence of calcineurin inhibition, graft vasculopathy is dependent on CD8(+) T cell effector mechanisms. In this study we examine the etiology of graft vasculopathy by these CD8(+) T cells in the presence of calcineurin inhibition. We transferred CD8(+) T cells from CyA treated IFN-gamma deficient mice into immunodeficient mouse recipients of aortic allografts to demonstrate that IFN-gamma production by CD8(+) T cells is essential for the development of AV in the presence of calcineurin inhibition. Using two models of CTL ablation we also demonstrated that CTL activity by CD8(+) T cells is essential for the development of AV in the presence of calcineurin inhibition. This is in contrast to models without calcineurin inhibitor immunosuppression where either pathway is capable, by itself, of inducing AV. These data indicate that although calcineurin inhibition ablates CD4(+) T cell effects and weakens CD8(+) T cell pathways, the antigenic challenge of the graft is enough to induce sufficient responsiveness from CD8(+) T cells to induce robust AV.
Nejat
Sara
S
Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4H7.
Zaki
Amr
A
Hirsch
Gregory M
GM
Lee
Timothy D G
TD
D000818:Animals; D001012:Aorta, Abdominal / Q000276:immunology / Q000473:pathology / Q000637:transplantation*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014184:Transplantation, Homologous
D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D007371:Interferon-gamma; D016572:Cyclosporine