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 a utoimmune syndrome with pathology identical to graft-vs-host disease ( GVHD). This syndrome can be induced both in man and in rats and is ass ociated with the development of cytolytic autoreactive T cells that re cognize 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 depende nt clonal deletion of autoreactive T lymphocytes by CsA and the elimin ation of a peripheral regulatory mechanism by the preparative regimen. The absence of peripheral autoregulation creates a permissive environ ment for the activation of the autoreactive T cells. Based on our unde rstanding of the immunobiology of this autoimmune syndrome, we have ut ilized the induction of autologous/syngeneic GVHD in an attempt to pro vide an antitumor therapeutic effect after autologous BMT. Interim ana lyses of our clinical trials suggest that this approach is quite promi sing.