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.

Aging and the immune response to organ transplantation

“…Moreover, deletions of MyD88 in donor animals or the graft have been shown to reduce alloimmunity (34). These studies demonstrate that TLR signaling via MyD88 is a central pathway controlling innate and subsequent adaptive alloimmunity (35).…”

Exploration ofα1-Antitrypsin Treatment Protocol for Islet Transplantation: Dosing Plan and Route of Administration

“…Other binding targets of hAAT include a set of danger-associated molecular pattern molecules (DAMPs), which predominate at sites of cell injury and act as immune adjuvants (Braza et al, 2016), including gp96 and HSP70 (Finotti and Pagetta, 2004; Ochayon et al, 2013). Based on this attribute, it is possible that the narrow surge in hAAT levels would be inferior to its constant supply, in a manner that accommodates local DAMP sequestration.…”

Nucleic acid scavenging microfiber mesh inhibits trauma-induced inflammation and thrombosis

“…DAMPs influence not only disease progress in primary injured sites but also facilitate dysfunction of other organs and systemic complications [40]. Furthermore, negatively charged DAMPs, including hyaluronic acid, cell-free nucleic acids and heparan sulfate, released after allograft reperfusion induced inflammation and thrombosis, which have a negative impact on transplant outcomes [47] and facilitate pulmonary dysfunction and graft-versus-host disease after allogeneic transplantation [41]. Moreover, elevated circulating DAMPs were shown to correlate with the onset of septic shock and organ failure in patients with sepsis [48].…”