CD47: a new player in phagocytosis and xenograft rejection

Abstract

Organ transplantation is limited by the availability of human donor organs. The transplantation of organs and tissues from other species (xenotransplantation) would supply an unlimited number of organs and offer many other advantages for which the pig has been identified as the most suitable source. However the robust immune responses to xenografts remain a major obstacle to clinical application of xenotransplantation. The more vigorous xenograft rejection relative to allograft rejection is largely accounted for by the extensive genetic disparities between the donor and recipient. Xenografts activate host immunity not only by expressing immunogenic xenoantigens that provide the targets for immune recognition and rejection, but also by lacking ligands for the host immune inhibitory receptors. This review is focused on recent findings regarding the role of CD47, a ligand of an immune inhibitory receptor SIRPα, in phagocytosis and xenograft rejection.

A drug development perspective on targeting tumor‐associated myeloid cells

“…Several hematological and solid tumors also express CD47 and are thereby protected from phagocytes. Preclinical data using antibodies that blocked human CD47 showed increased tumor cell phagocytosis and remarkable tumor growth inhibition in several xenograft models in mice and other species . Similar effects have been reported in syngeneic mouse models .…”

GalT‐KO pig lungs are highly susceptible to acute vascular rejection in baboons, which may be mitigated by transgenic expression of hCD47 on porcine blood vessels

“…In this study, we have attempted to prolong survival of porcine XLTx in baboons by combined strategies, consisting of (i) utilizing 4 different genetically modified porcine lungs, especially focusing on the role of hCD47 expression in donor lung grafts, and (ii) utilizing an induction immunosuppressive regimen that is similar to that of the xeno‐kidney transplant model that has achieved an average of longer than 4‐month survival of life‐supporting GalT‐KO alone kidney grafts in baboons . In designing this strategy, we reasoned (i) that hCD47 expression might overcome problems caused by the known species incompatibility of porcine CD47 and the primate homolog of its ligand, signal regulatory protein alpha (SIRPα) and (ii) that hCD55 or hCD46 would mitigate the complement‐mediated effects of natural anti‐pig antibodies. We also tested whether vascularized thymic grafts from the same donors might facilitate prolonged xenograft lung survival by minimizing primate anti‐pig T‐cell responses .…”

What’s hot, what’s new: Report from the American Transplant Congress 2017

“…They also recognize and reject allogeneic cells in transplant settings (bone marrow and solid organ transplants) via "missing self" recognition of allogeneic nonself. 63 The authors showed that transplantation of Non-Obese Diabetes (NOD) (H-2 g7 ) cell aggregates into Rag-/γc-/mice (H-2 b ) that are deficient for all adaptive cells, host monocytes responded to allogeneic NOD cells by differentiating into mature dendritic cells. 61 This is an emerging area of investigation, and progress in this area will have enormous impact in transplantation.…”