Inhibition of inflammation by IL-6 blockade in xenotransplantation

The inflammatory cytokine interleukin 6 (IL-6) plays a role in both acute and chronic organ allotransplant rejection. Data suggest that IL-6 inhibition may help prevent or reverse rejection, with large multi-center trials now underway. However, the evidence for the benefit of IL-6 inhibitors in xenotransplantation is limited. IL-6 inhibition has been explored in nonhuman-primate models of xenotransplantation, but no clear consensus exists on its efficacy or the best mode of IL-6 inhibition (anti-IL-6 antibodies, or through IL-6 receptor [IL-6R] blockade). Extra considerations for IL-6 blockade exist in xenotransplantation, as both recipient (human) and xenograft-derived (porcine) IL-6 may play roles. The systemic inflammation seen in xenograft recipients (SIXR) contributes to significant morbidity and mortality for the recipient through coagulation dysfunction and augmentation of the immune response. Anti-IL-6 antibodies (e.g., siltuximab) bind to human IL-6 and prevent IL-6R activation, but do not bind to porcine IL-6, and so have no effect in preventing graft-driven inflammatory processes. In contrast, IL-6R inhibitors (e.g., tocilizumab) inhibit IL-6 activity by blocking binding of human and porcine IL-6 to human IL-6R. Although IL-6R blockade cannot prevent the effect of IL-6 on porcine cells, it probably prevents graft-derived IL-6 from contributing to an inflammatory response in the host. This review outlines the role of IL-6 in xenotransplantation and discusses mechanisms for inhibiting IL-6 to improve recipient survival.