Aortic allograft vasculopathy is mediated by CD8(+) T cells in Cyclosporin A immunosuppressed mice

We investigated the role of CD4(+) T cells and CD8(+) T cells in mediating allograft vasculopathy in Cyclosporin A (CyA) immunosuppressed mice. We first established that a dose of 50 mg/kg/d CyA was required to prevent acute rejection in C57BL/6 mice. CyA given at 50 mg/kg/d did not prevent allograft vasculopathy in either cardiac or aortic transplants in these mice. Using CD4(-/-) and CD8(-/-) mice, we established that CyA immunosuppression at this dose was only effective at preventing allograft vasculopathy in mice lacking CD8(+) T cells. This implicates CD8(+) T cells in the development of AV in situations of clinical cardiac transplantation where CyA is still the mainstay of immunosuppressive therapy. We confirmed the important role for CD8(+) T cells in AV in the face of CyA immunosuppression by allopriming mice in the presence of CyA and transferring alloprimed T cells into RAG1(-/-) immunodeficient mice. The RAG1(-/-) mice were also treated with CyA. In this situation (CyA present during the allopriming and in the recipient), only primed CD8(+) T cells could mediate AV, primed CD4(+) T cells could not. Alloprimed CD8(+) T cells raised in the presence of CyA exhibited markedly reduced direct recognition responses (as measured by MLR) and effector responses (as measured by cytotoxic activity). In contrast indirect activation was retained. We interpret these data to suggest that in the face of CyA immunosuppression CD4(+) T cell effector function is ablated while CD8(+) T cell function remains partially intact. The in vitro data suggest that the indirect pathway remains intact in this population of CyA resistant CD8(+) T cells.