Autoimmune-mediated vasculopathy

The use of the immunosuppressive drug cyclosporine A (CsA) in solid organ t ransplantation can be associated with the development of vasculopathy as pa rt of the complex immune response involved in chronic rejection, including autoimmune recognition. Although CsA can directly affect endothelial cells, this drug alters the T cell repertoire promoting autoimmune recognition. T he present studies evaluated the ability of CsA-induced autoreactive T cell s to mediate vascular lesions in syngeneic heart grafts. Graft vasculopathy developed in syngeneic heart grafts following either the primary induction of autoimmunity with CsA or the adoptive transfer of CsA-induced autoreact ive T cells. Initially, an inflammatory response occurred in the medial wal l of the small arterial vessels, accompanied by a perivascular lymphocytic infiltrate (including a lymphocytic infiltrate into the myocardium), follow ed by progression of vascular disease with endothelial cell proliferation. The development and progression of vascular disease correlated with the cyt okine profile of the infiltrating lymphocytes with type 1 cytokines detecte d early and type 2 cytokines detected as the disease progressed. Initiation of this response correlated with upregulation of the target antigen recogn ized by the CsA-induced autoreactive T cells, the MHC class II-invariant ch ain peptide complex. This antigen complex, when upregulated on endothelial cells by interferon, allowed effective targeting by the autoreactive T lymp hocytes, Strategies to inhibit the upregulation of MHC class II antigens by treatment of the recipients with chloroquine truncated the disease process . The results of these studies suggest that CsA-induced autoreactive mechan isms can contribute to the development of graft vasculopathy. (C) 2001 Acad emic Press.