Induction of oral tolerance in splenocyte recipients toward pretransplant antigens ameliorates chronic graft versus host disease in a murine model

Chronic graft versus host disease (cGVHD) is a major complication that can develop after bone marrow transplantation. It involves an immune-mediated a ttack by transplanted donor lymphocytes, and often results in inflammatory damage of host target organs. immune hyporesponsiveness induced by oral ant igen administration has been recently shown to prevent the development of c GVHD in a murine model. The aim of this study was to evaluate whether toler ance induction in bone marrow transplant (BMT) recipients after transplanta tion, toward their pretransplant antigens, can alleviate preexisting cGVHD in a mouse model. cGVHD was generated by infusing 2.5 x 10(7) splenocytes f rom B10.D2 donor mice, to sublethally irradiated (6 Gy) BALB/c recipient mi ce, which differ by minor histocompatibility antigens. Transplantation resu lted in cGVHD, with characteristic scleroderma-like cutaneous fibrosis, inc reased skin collagen content, decreased body weight, and hepatic and small bowel inflammation. Oral tolerance was induced by feeding recipient BALB/c mice with proteins extracted from BALB/c splenocytes for 11 days after B10. D2 splenocyte transplantation. Tolerance induction was evidenced by a signi ficant reduction in mixed lymphocyte response of effector splenocytes from tolerant BALB/c mice transplanted with B10.D2 splenocytes against BALB/c ta rget splenocytes. Oral tolerance decreased skin collagen deposits. Reductio n of collagen (alpha 1(1)) gene expression and skin collagen were shown by in situ hybridization and histochemistry, respectively. Liver and bowel bio psy specimens revealed less inflammation. Serum IL-10 levels were higher in tolerant mice than in controls, whereas IFN gamma was significantly reduce d. Oral tolerance of BMT recipients toward their pretransplant antigens aft er splenocyte transplantation down-regulated the immune attack by transplan ted cells, thus ameliorating cGVHD. (Blood. 2000;95: 3613-3619) (C) 2000 by The American Society of Hematology.