Immunobiology and immunotherapeutic implications of syngeneic/autologous graft-versus-host disease.
Administration of the immunosuppressive drug cyclosporine (CsA) after syngeneic/autologous bone marrow transplantation (BMT) elicits an autoimmune syndrome with pathology virtually identical to graft-vs-host disease (GVHD). The induction of this syndrome, termed syngeneic/autologous GVHD, is a two-tiered process requiring both the active inhibition of thymic-dependent clonal deletion and the elimination of mature T cells that have an immunoregulatory effect. Eradication of the peripheral immunoregulatory compartment by the preparative regimen provides a permissive environment for the activation of the syngeneic/autologous GVHD effector T cells. Although the repertoire of autoreactive effector T lymphocytes is highly conserved, these T cells promiscuously recognize MHC class II determinants. This novel specificity of the autoreactive lymphocytes appears to be dependent on the peptide derived from the MHC class II invariant chain. Recent studies also suggest that these promiscuous autoreactive T cells can effectively target and eliminate MHC class II-expressing tumor cells. Administration of cytokines that upregulate the target antigen or expand the effector population can potentiate the antitumor activity of syngeneic/autologous GVHD. Although the induction of syngeneic/autologous GVHD is an untoward effect of CsA immunosuppression, mobilization of these autoimmune mechanisms provides a promising immunotherapeutic approach for certain neoplastic diseases.
Hess
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AD
Division of Hematologic Malignancies Oncology Center, Johns Hopkins University, Baltimore, MD 21287-8985, USA.
Thoburn
C J
CJ
D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology* / Q000628:therapy*; D006801:Humans; D007167:Immunotherapy / Q000639:trends; D014185:Transplantation, Isogeneic / Q000009:adverse effects*