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.
Hess
A D
AD
Bone Marrow Transplant Unit, Johns Hopkins University, Baltimore, MD 21287-8985.
Jones
R C
RC
Santos
G W
GW
D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology / Q000473:pathology; D016572:Cyclosporine / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D006086:Graft vs Host Disease / Q000209:etiology / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D051381:Rats; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D014182:Transplantation, Autologous / Q000502:physiology
D000949:Histocompatibility Antigens Class II; D016572:Cyclosporine