Cyclosporine-induced syngeneic graft-vs-host disease: Prevention of autoaggression by treatment with monoclonal antibodies to t lymphocyte cell surface determinants and to mhc class ii antigens

Abstract Administration of cyclosporine (CsA) following syngeneic/autologous bone marrow transplantation (BMT) elicits a T lymphocyte-dependent autoimmune disease resembling graft-vs-host disease (syngeneic GVHD). This autoaggression syndrome appears to be due to the autorecognition of self-MHC class II antigens by CD8+ cytolytic T cells and a CD4+ autoreactive T cell subset. The syngeneic GVHD model was used to assess the effectiveness of treatment with monoclonal antibodies to the α/β T cell receptor (TCR) and the CD4 or CD8 determinants on the prevention of autoimmune disease. Nylon wool nonadherent splenic T cells (50 × 106) from Lewis strain rats with active syngeneic GVHD were adoptively transferred into irradiated (1050 rad syngeneic recipients reconstituted with normal marrow (60 × 106 cells). Monoclonal antibody (McAb) to the α/β TCR, the CD4 determinant, or the CD8 determinant was administered to secondary recipients on Days 0, 3, 6, 9, and 12 at a dose of 0.1 ml of ascites fluid. Control animals received normal mouse serum on the same schedule. Animals treated with either saline or normal mouse serum developed syngeneic GVHD within 16-20 days. Comparatively, syngeneic GVHD developed much later in the secondary recipients treated with anti-CD4 McAb (onset of syngeneic GVHD, 28-32 days) and was less severe compared to the control group. On the other hand, the recipients treated with McAb's to the α/β TCR or to the CD8 determinant did not develop syngeneic GVHD (monitored over 10 weeks post-therapy). Peripheral blood lymphocytes from these recipients also were analyzed for T cell subsets by phenotypic analysis. There was a pronounced reduction of the total number of cells expressing the α/β TCR and the CD8 determinant after treatment of the recipients with the McAb's to the α/β TCR and to the CD8 determinant, respectively. Recovery to normal levels began to occur 6 weeks after the last dose of McAb. There was a significant reduction of the CD4+ subset after treatment with anti-CD4 McAb, but it was not long lasting with recovery coinciding with the onset of syngeneic GVHD. Studies were also performed to evaluate McAb therapy of established syngeneic GVHD. The McAb's were found to be largely ineffective due in part to pulmonary toxicity. Furthermore, this model was utilized to evaluate the efficacy of treatment with McAb to the target antigen of syngeneic GVHD. Infusion of McAb to a public determinant on class II MHC molecules prevented or significantly delayed the onset of syngeneic GVHD after adoptive transfer of effector cells. McAb to MHC class I determinants were ineffective. Additional studies from F1 → parent chimeras with syngeneic GVHD support the hypothesis that the target in this autoaggression syndrome is a public determinant on class II MHC antigens. The results suggest that syngeneic GVHD requires the participation of both the CD8 and CD4 T cell subsets. Limiting the CD4+ T cell subset which amplifies the CD8+ cells by treatment with anti-CD4 McAb only retarded the onset of syngeneic GVHD. On the other hand, treatment with anti-CD8 or anti-α/β TCR McAb's completely prevented the development of this autoaggression syndrome by eliminating the cell population which initiates the autoimmunemediated tissue damage. Similarly, treatment with McAb to the target antigen in syngeneic GVHD also was an effective means for preventing or retarding onset of disease.