Innate Immunity and Resistance to Tolerogenesis in Allotransplantation

Abstract

The development of immunosuppressive drugs to control adaptive immune responses has led to the success of transplantation as a therapy for end-stage organ failure. However, these agents are largely ineffective in suppressing components of the innate immune system. This distinction has gained in clinical significance as mounting evidence now indicates that innate immune responses play important roles in the acute and chronic rejection of whole organ allografts. For instance, whereas clinical interest in natural killer (NK) cells was once largely confined to the field of bone marrow transplantation, recent findings suggest that these cells can also participate in the acute rejection of cardiac allografts and prevent tolerance induction. Stimulation of Toll-like receptors (TLRs), another important component of innate immunity, by endogenous ligands released in response to ischemia/reperfusion is now known to cause an inflammatory milieu favorable to graft rejection and abrogation of tolerance. Emerging data suggest that activation of complement is linked to acute rejection and interferes with tolerance. In summary, the conventional wisdom that the innate immune system is of little importance in whole organ transplantation is no longer tenable. The addition of strategies that target TLRs, NK cells, complement, and other components of the innate immune system will be necessary to eventually achieve long-term tolerance to human allograft recipients.

Immunosenescence and Immune Response in Organ Transplantation

“…There is increasing data on the importance of the innate immune response in both rejection and tolerance [63–69]. All of components of the innate immune system are also affected by advanced age [70–73].…”

Cardiac allograft immune activation: current perspectives

“…5 Cells of the innate immune system interact against a defined set of molecules including pathogen-associated molecular patterns in the context of infection and damage-associated molecular patterns in the process of tissue injury. Toll-like receptors (TLRs) are one type of pattern-recognition receptor (PRR) involved in initiation and amplification of innate immune responses.…”

The Innate Immune System: Its Rediscovery before Toll Was Described

“…Although in earlier times heavily opposed and later on notoriously neglected by the transplant community, our Injury Hypothesis has just recently gained center stage and obviously appears well accepted by leading transplant immunologists [22,23] . Time seems now to be ripe to think of new immunosuppressive strategies in organ transplantation such as interfering with the donor's innate immune system during organ removal and the recipient's innate immune system during allograft reperfusion, for example with the use of antioxidants, anti-IL-1 ␤ inhibitors, anticomplement agents, and polyclonal antilymphocyte preparations.…”