Innate allorecognition

Abstract

Summary Vertebrates mount strong adaptive immune responses to transplanted organs (allografts), but the mechanisms by which the innate immune system initiates this response are not completely understood. In anti-microbial immunity, non-self molecules associated with pathogens but not present in the host induce the maturation of innate antigen-presenting cells (APCs) by binding to germ-line-encoded receptors. Mature APCs then initiate the adaptive immune response by presenting microbial antigen and providing costimulatory signals to T cells. How allografts activate APCs, however, is less clear, because allografts are presumably sterile. A widely accepted view is that inflammatory or ‘danger’ molecules released by dying graft cells at the time of transplantation trigger APC maturation and the T-cell response that follows. Alternatively, it has been proposed that the introduction of microbial products during the surgical procedure could also alert the innate immune system to the presence of the transplanted organ. Here we review why these hypotheses fail to fully explain how the alloimmune response is initiated after transplantation and summarize evidence that recognition of allogeneic non-self by monocytes is a key event in triggering alloimmunity and graft rejection.

Innate Allorecognition Results in Rapid Accumulation of Monocyte-Derived Dendritic Cells

“…However, this conjecture does not easily explain several observations. It does not explain why only allogeneic grafts can induce more profound and sustained responses (9,12). It also does not explain why the removal or dissipation of danger signals does not prevent alloresponses.…”

“…The immune system is also capable of discriminating between self-and non-self-tissues from individuals of the same species, a process known as allorecognition (9). This is particularly important in the setting of organ transplantation, where allografts are subjected to immunological rejection through various mechanisms, including cell-and Ab-mediated processes (10).…”

“…As such, it has been proposed that danger signals induced by surgical, ischemic, and other iatrogenic damage to host and graft tissue could contribute to the immunological response (11). In support of this, even syngeneic grafts can induce an initial immune response at graft sites (9,12). However, this conjecture does not easily explain several observations.…”

“…Recently, the concept that the innate immune system can inherently detect allogeneic tissue without the need for external danger or microbial signals has been proposed (9,14). A recent study (15) found that monocytes can innately respond in the setting of allogeneic heart and kidney transplantation.…”

A Brief Journey through the Immune System

“…distinguishes between self and allogeneic nonself are not entirely clear and will surely intrigue the inquisitive minds of your descendants (26).…”