Many potential recipients with high-preformed human leukocyte antigen antibody levels wait significantly longer than unsensitized patients for a compatible donor kidney or are even worse; patients remain on dialysis indefinitely. Over the past few years, promising desensitization protocols have been developed that permit positive-crossmatch transplantation. These protocols include treatment with high doses of intravenous immunoglobulin, anti-CD20 antibodies, T-cell depletion strategies, plasma cell depletion, plasmapheresis, and complement blockade (1). An alternative approach has been developed in Sweden by Olausson et al. (2) and is based on combined auxiliary liver-kidney transplantation (3). The auxiliary liver from the same donor as the kidney is transplanted before the kidney transplantation with the purpose of protecting it form hyperacute rejection. This procedure might raise ethical questions of organ allocation. Nevertheless, none of the 10 transplanted patients hyperacutely rejected their kidney. The auxiliary liver did not prevent alloreactivity because 6 of 10 patients had an acute rejection episode, and 2 of these 6 patients lost their kidney allograft (3). One of the failed kidneys developed untreatable graft function deterioration after a complication that led to the removal of the auxiliary liver, suggesting a protective liver effect. An explanation for the relatively good results seen in this study is that the liver absorbs the preformed antibodies against donor human leukocyte antigens, the so-called sponge theory. Certainly, donor-specific antibodies disappeared in some but not all patients. This observation suggests that other mechanisms contribute to the protective role of auxiliary liver. In this issue of Transplantation, Ingelsten et al. (3) report on other mechanism. Liver-induced kidney graft acceptance is associated with an inflammatory liver response. Within hours after transplantation, the grafted liver but not the transplanted kidney was infiltrated with recipient CD3+ T cells and CD68+ macrophages and showed increased expression of nuclear factor κB-associated genes and indoleamine 2,3-dioxygenase. This enzyme is overexpressed in response to proinflammatory cytokines such as interferon-γ and may cause immunosuppression through breakdown of tryptophan in the liver microenvironment (3). Interestingly, the inflammatory response was particularly seen in livers of patients who did not acutely reject the transplanted kidney. This once again shows that immune activation is required to initiate responses that are key for donor-specific immunologic quiescence. In that hypothesis, the CCL20 findings nicely fit. It is intriguing that in the auxiliary liver of nonrejectors, the nuclear factor κB-dependent chemokine CCL20 is strongly up regulated. CCL20 is chemotactic for T cells including inflammatory T helper 17 cells and regulatory FoxP3+ T cells, B cells, and dendritic cells, and weakly for neutrophils (4). Thus, shortly after transplantation, the liver consists of chemokines that attract functionally different immune cells, is not rejected, and prevents the transplanted kidney from acute rejection. Therefore, FoxP3+ T cells might have infiltrated the liver and suppress the inflammatory activities of effector T cells. For instance, during acute rejection, FoxP3+ T cells home in the transplanted organ and effectively control aggressive intragraft antidonor immune reactivity (5). Furthermore, it could well be that in the auxiliary liver, other cell populations are present that inhibit inflammatory responses. Regulatory macrophages and natural killer cells have been identified that by themselves or in combination with liver-specific populations such as Kupffer cells contribute to the observed phenomenon. Overall, the data suggest that the transplanted auxiliary liver dampens the antidonor kidney response by a cascade of different mechanisms starting with the absorption of preexisting antidonor antibodies followed by indoleamine 2,3-dioxygenase activation and regulation by liver specific cells and FoxP3+ T cells. What is needed now is proof of principle: analysis of the T-cell compartment. What is the role of the observed T-cell infiltrate in the prevention of alloreactivity (3)? Are both effector T cells and suppressive FoxP3+ T cells present in the auxiliary liver? What is the specificity of the T cells? If indeed FoxP3+ regulatory T cells are involved in the control of immune responses, it might open the door for regulatory T-cell promoting drugs such as rapamycin, or even cell-based induction therapy in highly sensitized patients on the wait list. The unique setting of auxiliary liver-kidney transplantation provides the rare opportunity to study the mechanisms by which the human immune system suppresses aggressive alloreactivity.