Role of TLRs and DAMPs in allograft inflammation and transplant outcomes

Abstract

Graft inflammation impairs the induction of solid organ transplant tolerance and enhances acute and chronic rejection. Elucidating the mechanisms by which inflammation is induced after organ transplantation could lead to novel therapeutics to improve transplant outcomes. In this Review we describe endogenous substances--damage-associated molecular patterns (DAMPs)--that are released after allograft reperfusion and induce inflammation. We also describe innate immune signalling pathways that are activated after solid organ transplantation, with a focus on Toll-like receptors (TLRs) and their signal adaptor, MYD88. Experimental and clinical studies have yielded a large body of evidence that TLRs and MYD88 are instrumental in initiating allograft inflammation and promoting the development of acute and chronic rejection. Ongoing clinical studies are testing TLR inhibition strategies in solid organ transplantation, although avoiding compromising host defence to pathogens is a key challenge. Further elucidation of the mechanisms by which sterile inflammation is induced, maintained and amplified within the allograft has the potential to lead to novel anti-inflammatory treatments that could improve outcomes for solid organ transplant recipients.

Figure 1 |. Inflammation initiation and maintenance after organ transplantation.

Ischaemia–reperfusion injury (IRI) induces a degree of graft cell necrosis and breakdown of the extracellular matrix. These processes lead to the release of damage-associated molecular patterns (DAMPs), which can heighten the intragraft inflammatory milieu by activating innate immune signalling pathways via the toll-like receptors (TLR). Graft cells (vascular endothelial cells, macrophages and dendritic cells) upregulate adhesion molecules (such as VCAM-1 and L-selectin) and co-stimulatory molecules (such as CD80). They also secrete inflammatory cytokines (such as IL-6 and TNF), which enhance immune cell recruitment into the graft and activate activate recipient cells to produce amplifiers of inflammation such as haptoglobin, which enter the circulation and amplify inflammation within the transplant. This increased inflammation further activates graft resident or infiltrated immune cells and induces their migration to the draining lymph nodes where they can activate naive anti-donor T cells to initiate adaptive anti-donor immune responses. The inflammatory reaction triggered by IRI can ultimately lead to graft rejection.