Autologous graft-vs-host disease: mechanisms and potential therapeutic effect

Administration of the immunosuppressive drug cyclosporine (CsA) after autologous or syngeneic bone marrow transplantation (BMT) elicits an autoimmune syndrome with pathology identical to graft-vs-host disease (GVHD). This syndrome can be induced both in man and in rats and is associated with the development of cytolytic autoreactive T cells that recognize MHC class II determinants. Studies in a rat model suggest that there are two essential components necessary for the induction of an autologous/syngeneic GVHD and include the inhibition of thymic dependent clonal deletion of autoreactive T lymphocytes by CsA and the elimination of a peripheral regulatory mechanism by the preparative regimen. The absence of peripheral autoregulation creates a permissive environment for the activation of the autoreactive T cells. Based on our understanding of the immunobiology of this autoimmune syndrome, we have utilized the induction of autologous/syngeneic GVHD in an attempt to provide an antitumor therapeutic effect after autologous BMT. Interim analyses of our clinical trials suggest that this approach is quite promising.