Inflammatory triggers of acute rejection of organ allografts

Abstract

Solid organ transplantation is a vital therapy for end stage diseases. Decades of research have established that components of the adaptive immune system are critical for transplant rejection, but the role of the innate immune system in organ transplantation is just emerging. Accumulating evidence indicates that the innate immune system is activated at the time of organ implantation by the release of endogenous inflammatory triggers. This review discusses the nature of these triggers in organ transplantation and also potential mediators that may enhance inflammation resolution after organ implantation.

Keywords: inflammation; organ transplantation; resolution.

Fig. 1. The process of organ harvest and implantation induces injury in the transplant

Changes to an organ occur at the time of brain death where a series of inflammatory changes occur within the organ. The procurement and transit of the organ imparts a further ischemic injury, which is exacerbated at the time of implantation when reperfusion exacerbates the injury to the transplant (known as ischemia reperfusion injury). Injury to the transplant leads to the release of inflammatory triggers that are sensed by immune and non-immune cells to initiate the inflammatory response to the transplant.

Fig. 2. The balance of initiation of inflammation and inflammation resolution after organ implantation

The release of inflammatory triggers within the organ induces inflammation. Several inflammatory triggers have been identified as inducing inflammation after organ transplantation (e.g. HMGB1)(Table 1). These triggers are sensed by immune cells (e.g., macrophages and DCs) and non-immune cells (e.g. epithelial cells) and transduce inflammatory signals via a variety of pathways that are downstream of the TLRs and inflammasome. Many inflammatory triggers released after organ transplantation are likely yet to be identified, and the inflammatory pathways that induce inflammation after organ transplantation are still to be fully elucidated. Several pathways are activated after organ transplantation that inhibit further inflammation. Furthermore, certain immune cells (e.g. macrophages) many change their phenotype to one of resolution by secreting mediators that enhance the clearance of apoptotic cells and impair further recruitment of inflammatory cells into the transplant.