Extracellular histones and xenotransplantation

Abstract

Xenotransplantation may be an alternative source of organs for patients with end‐stage organ failure, but problems remain to be overcome. Five factors that are problematic are (a) a sustained systemic inflammatory response in the xenograft recipient, (b) thrombotic microangiopathy and disseminated intravascular coagulation, (c) ischemia‐reperfusion injury, (d) complement activation, and (e) vascular endothelial cell injury. In xenotransplantation, histones, which are positively charged proteins, are released into the extracellular space from damaged and activated cells, cause cell and tissue damage, and act as danger/damage‐associated molecular patterns (DAMPs) that mediate inflammation, coagulation disorders, an immune response, and cytotoxicity. We have previously demonstrated that serum histones increase after pig‐to‐baboon organ transplantation and infection. Treatment of the recipient with tocilizumab (interleukin‐6 receptor blockade) reduces the level of serum histones and C‐reactive protein. In this review, the potential role of extracellular histones in xenotransplantation is discussed, and we briefly summarize the relationship between extracellular histones and the inflammatory response, coagulation dysfunction, ischemia‐reperfusion injury, the complement system, and vascular endothelial cell injury.

A perspective on the potential detrimental role of inflammation in pig orthotopic heart xenotransplantation

“…Extracellular histones are released as a result of insults such as trauma or ischemia‐reperfusion, but have also been demonstrated to be elevated after pig organ xenotransplantation 37,38 . They bind to cell surface (toll‐like) receptors and result in cell death by NETosis.…”

Xenotransplantation literature update for September – October 2020

“…Circulating histone levels increase after pig kidney transplants in baboons on post‐operative day 5 supporting the hypothesis that histones are part of a common pathway contributing to graft rejection as well as harm to the recipient 29 . However, if the histones could be scavenged or neutralized at the time of xenotransplantation, the consequences could be reduced, and graft survival enhanced 28 …”

“…Histones are positively charged proteins and released into the extracellular space from damaged cells and can mediate an inflammatory response and cytotoxicity 24‐27 . Li et al review histones as damage associated molecular patterns (DAMPs) and induce endothelial dysfunction, injury, and organ failure 28 . They mediate neutrophil margination, platelet aggregation, and micro‐ and macro‐thrombosis 24‐27 .…”

Developments in kidney xenotransplantation

“…Compared with the understanding of the alloimmune response, that of the heterologous immune mechanism is still in its infancy ( 128 , 129 ). We believe that a deeper understanding of immunological theories and the development of techniques will continue to promote the progress of kidney xenotransplantation.…”