Oral tolerization ameliorates liver disorders associated with chronic graft versus host disease in mice

In chronic graft versus host disease (cGVHD), an immune attack by transplanted donor lymphocytes results in damage of host target organs. A disbalance between proinflammatory (Th1) and anti-inflammatory cytokines (Th2) plays an important role in the pathogenesis. Immune hyporesponsiveness induced by oral antigen administration has been shown to suppress autoimmunity. We evaluated the efficacy of oral tolerization in preventing cGVHD in a mouse model. cGVHD was generated by infusing 2.5 x 10(7) splenocytes from B10.D2 donor mice, to sublethally irradiated (6 Gy) BALB/c recipient mice, which differ in minor histocompatibility antigens. The transplantation resulted in cGVHD, with characteristic hepatic and small bowel inflammation, and increased skin collagen content and fibrosis. Oral tolerance was induced by feeding donor B10.D2 mice with proteins extracted from BALB/c splenocytes at 50 microg/d per mouse for 11 days before transplantation. Tolerization was evidenced by reduction in mixed lymphocyte response of effector splenocytes from tolerized B10.D2 mice against BALB/c target splenocytes. Liver and small bowel biopsy specimens revealed much less inflammation. Oral tolerization prevented weight and subcutaneous fat loss, reduced thickening, and skin collagen deposits. Reduction of collagen alpha1 (I) gene expression was shown by in situ hybridization. Serum interleukin 10 (IL-10) levels measured significantly higher in tolerized mice than in controls, whereas interferon gamma (IFN-gamma), IL-2, and tumor necrosis factor alpha (TNF-alpha) were reduced significantly. Oral tolerization of splenocyte donors towards recipient-strain splenocytes ameliorated cGVHD of the liver, small intestine, and skin. A cytokine shift from a proinflammatory to an anti-inflammatory pattern may play a role in down-regulation of the immune-mediated target organ damage.