Concanavalin A (Con A) is a lectin originating from the jack-bean and well known for its ability to stimulate T cells and induce autoimmune hepatitis. We previously demonstrated the induction of immunosuppressive antinuclear autoantibody in the course of Con A-induced transient autoimmune hepatitis. This study aimed to clarify the effects of Con A-induced hepatitis on liver allograft rejection and acceptance. In this study, we observed the unique phenomenon that the induction of transient de novo autoimmune hepatitis by Con A injection paradoxically overcomes the rejection without any immunosuppressive drug and exhibits significantly prolonged survival after orthotopic liver transplantation (OLT). Significantly increased titers of anti-nuclear Abs against histone H1 and high-mobility group box 1 (HMGB1) and reduced donor specific alloantibody response were observed in Con A-injected recipients. Induction of Foxp3 and IL-10 in OLT livers of Con A-injected recipients suggested the involvement of regulatory T cells in this unique phenomenon. Our present data suggest the significance of autoimmune responses against nuclear histone H1 and HMGB1 for competing allogeneic immune responses, resulting in the acceptance of liver allografts in experimental liver transplantation. 1. Introduction Liver is permanently exposed to gut-derived antigens, including pathogens, toxins, and harmless food antigens, and immune responses against the dietary or bacterial antigens from the gut are unusual [1, 2]. However, the immune system should be activated to prevent liver damage when the liver is suffering from harmful pathogens such as hepatitis B and C viruses. The mechanisms for balancing tolerance and immunity in the liver have not been fully elucidated, but the unique repertories of nonparenchymal cells including liver antigen-presenting cells (e.g., dendritic cells (DCs), Kupffer cells, and liver sinusoidal endothelial cells) and unconventional lymphoid cells (e.g., NK cells, B-1 cells, and γδ T cells) that are rarely present in the blood may explain the immune privilege of the liver [3]. Furthermore, it has been known that the liver does not always obey the normal rules of transplant rejection (Medawar’s rule of transplantation) [4]. In a rat orthotopic liver transplantation (OLT) model, Piebald Virol Glaxo (PVG) (MHC haplotype; ) recipients spontaneously accept donor Dark Agouti (DA) ( ) livers in the absence of extra immunosuppressive treatment, while other organ allografts in this combination are promptly rejected [5–7]. In contrast, recipient Lewis (LEW) ( ) rats
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