The tolerogenic properties of the liver have long been recognised, especially in regard to transplantation. Spontaneous acceptance of liver grafts occurs in a number of experimental models and also in a proportion of clinical transplant recipients. Liver graft acceptance results from donor antigen-specific tolerance, demonstrated by the extension of tolerance to other grafts of donor origin. A number of factors have been proposed to be involved in liver transplant tolerance induction, including the release of soluble major histocompatibility (MHC) molecules from the liver, its complement of immunosuppressive donor leucocytes, and the ability of hepatocytes to directly interact with and destroy antigen-specific T cells. The large tissue mass of the liver has also been suggested to act as a cytokine sink, with the potential to exhaust the immune response. In this review, we outline the growing body of evidence, from experimental models and clinical transplantation, which supports a role for large tissue mass and high antigen dose in the induction of tolerance. We also discuss a novel gene therapy approach to exploit this dose effect and induce antigen-specific tolerance robust enough to overcome a primed T cell memory response. 1. Liver Transplant Tolerance From the very first experimental liver transplants, it was clear that livers were less likely to be rejected than other transplanted organs [1]. In animal models, liver transplants are often accepted without requiring any treatment while other transplanted organs, such as hearts or kidneys, are rejected. This was first demonstrated in outbred pigs [1] and subsequently in inbred rats [2, 3] and mice [4]. Spontaneous acceptance of a transplanted liver leads rapidly to liver donor-specific tolerance in many models [1, 2, 5, 6]. This tolerance is particularly robust and rapidly induces acceptance of skin grafts from the liver donor strain [1, 5, 7, 8]. Moreover, a liver transplant can act like an immunosuppressive drug in reversing ongoing rejection of heart [9] or pancreas [10] transplants that are syngeneic with the liver donor. Clinical liver transplants also have a better outcome than transplants of other organs with a significant proportion of patients able to be removed from all immunosuppression [11, 12]. There have been many proposed mechanisms for the ability of the transplanted liver to be accepted by the recipient. Initially, it was thought that the high levels of soluble major histocompatibility (MHC) molecules produced by the donor liver were responsible for liver tolerance [13]. This has not
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