Pathogenesis of Cyclosporin A-induced autoimmunity: Absence of T-cell reactivity towards syngeneic antigen presenting cells

Cyclosporin A-induced autoimmunity (CsA-AI) is a T-cell mediated inflammatory autoimmune disease of the skin resembling human scleroderma and is often referred to as syngeneic-Graft-versus-Host Disease. Induction of CsA-AI is obtained by total body irradiation in combination with syngeneic bone marrow transplantation (BMT) and subsequent administration of CsA for 4 weeks; about 2 weeks after withdrawal of CsA disease develops. In CsA-AI, irradiation is thought to eliminate peripheral autoregulatory T-cells, whereas CsA interferes with selection in the thymus giving rise to putative autoreactive T-cells. MHC class II-self-peptide complexes have been thought to function as autoantigen(s). Moreover, induction of CsA-AI is used in humans to achieve a Graft-versus-Leukemia effect based on this anti-MHC class II reactivity. In this study we therefore have examined whether T-cells of CsA-AI rats respond to syngeneic dendritic cells (DC). Furthermore we determined the in vitro stimulatory capacity of the presumptive antigen presenting cell (APC) in the target organs, i.e. the keratinocytes. In contrast to keratinocytes of control rats the keratinocytes of CsA-AI rats show in situ a strong reactivity with anti-MHC class II specific monoclonal antibody (mAb) and therefore might induce local T-cell activation. Results reveal that T-cells of CsA-AI rats have no increased response to syngeneic DC. This indicates that MHC class II is not the autoantigen and that the autoantigen(s) are not presented by peripheral APC of control animals. With respect to possible APC in the target organ flowcytometry showed a strong induction of MHC class II and upregulation of MHC class I on keratinocytes of CsA-AI rats. However, these cells were unable to give any stimulatory signal to T-cells of control or diseased animals, indicating that the autoantigen(s) are not presented by keratinocytes of CsA-AI rats and that the MHC induction is probably secondary to the inflammatory reaction in the skin. The nature of the autoantigen(s) therefore remains to be determined.