There are a number of well-established paradigms in transplantation immunology. Transplants of organs or skin across a complete MHC mismatch are rejected unless the recipient is immunosuppressed. Passenger leukocytes within the graft are the main stimulators of this rejection (1, 2). A local increase in the cytokines interleukin (IL*)-2 and interferon (IFN)-γ occurs in rejection of a transplant, whereas a reduction in their expression is associated with graft tolerance (3-5). Liver transplants across major barriers break these paradigms because they are often not rejected, even in the absence of immunosuppression (6, 7). Moreover, liver passenger leukocytes seem to be required for this spontaneous form of graft acceptance (8-10), which is accompanied by rapid immune activation shortly after liver transplantation (11, 12). Surprisingly, up-regulation of IL-2 and IFN-γ in the lymphoid tissues of tolerant animals is much greater than in rejecting animals (12). Similar to liver allografts, multiple heart and kidney grafts to a single recipient are accepted, although when transplanted singly they are rapidly rejected (13). These paradoxical findings are consistent with activation-associated or high-zone tolerance akin to the high-zone tolerance to soluble antigens (14, 15) or alloantigens (16, 17) reported many years ago.