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 transplan ted 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 ev aluated the efficacy of oral tolerization in preventing cGVHD in a mouse mo del. cGVHD was generated by infusing 2.5 x 10(7) splenocytes from B10.D2 do nor mice, to sublethally irradiated (6 Gy) BALB/c recipient mice, which dif fer in minor histocompatibility antigens. The transplantation resulted in c GVHD, with characteristic hepatic and small bowel inflammation, and increas ed skin collagen content and fibrosis. Oral tolerance was induced by feedin g donor B10.D2 mice with proteins extracted from BALB/c splenocytes at 50 m u g/d per mouse for Ii days before transplantation. Tolerization was eviden ced by reduction in mixed lymphocyte response of effector splenocytes from tolerized B10.D2 mice against BALB/c target splenocytes, Liver and small bo wel biopsy specimens revealed much less inflammation. Oral tolerization pre vented weight and subcutaneous fat loss, reduced thickening, and skin colla gen deposits. Reduction of collagen alpha 1 (I) gene expression was shown b y in situ hybridization. Serum interleukin 10 (IL-10) levels measured signi ficantly higher in tolerized mice than in controls, whereas interferon gamm a (IFN-gamma), IL-2, and tumor necrosis factor alpha (TNF-alpha) were reduc ed significantly. Oral tolerization of splenocyte donors towards recipient- strain splenocytes ameliorated cGVHD of the liver, small intestine, and ski n. A cytokine shift from a proinflammatory to an anti-inflammatory pattern may play a role in down-regulation of the immune-mediated target organ dama ge.