Liver nonparenchymal cells involved in hyporesponsiveness induced by portal vein injection of alloantigen

INTRODUCTION: Intrahepatic injection of alloantigen prolongs allograft survival and inhibits T-lymphocyte release of both IL-2 and IFN-gamma but not IL-4. This suggests that intrahepatic processing of antigen lead to a predominance of Th2 cell population with inhibition of Th1 cell type. This study examines the effects of hepatic nonparenchymal cells (NPCs) on T cell function and cytokine mRNA expression profiles. MATERIALS AND METHODS: Following portal vein (p.v.) injection of allogeneic splenic mononuclear cells (SMNC) in mice, heterotopic cardiac allograft survival and donor-specific immune responses were assessed. The cytokine profiles were evaluated in heart grafts and spleens from transplanted mice, or in recipient lymphocytes stimulated in vitro with alloantigen. The immunoregulatory role of NPCs from p.v. injected mice was evaluated. RESULTS: Transplanted mice with prolonged graft survival demonstrated increased IL-4, TGF-beta and IL-10 and/or decreased IFN-gamma and IL-2 mRNA expression within the spleen and the transplanted graft. This correlated with increased antigen-specific IL-4, IL-10 and TGF-beta expression in lymphocytes isolated from the p.v. injected mice. In mixed lymphocyte cultures using NPC from p.v. injected mice as regulatory cells, there was decreased proliferation of lymphocytes from the p.v. injected mice in response to allogeneic stimulation, associated with increased IL-4, TGF-beta and IL-10 production and decreased IFN-gamma and IL-2 production. The regulatory effects of the NPC was reversed by prostaglandin E inhibitor. CONCLUSIONS: Interactions between allogeneic lymphocytes and NPCs results in an impaired Th1 response and preferential shift towards a Th2 cytokine response which may regulate allograft rejection.