Elimination of donor CD47 protects against vascularized allograft rejection in mice

Xenotransplantation. 2019 Mar;26(2):e12459. doi: 10.1111/xen.12459. Epub 2018 Aug 23.

Abstract

CD47 is a ubiquitously expressed transmembrane glycoprotein that plays a complex role in regulation of cell survival and function. We have previously shown that the interspecies incompatibility of CD47 plays an important role in triggering rejection of cellular xenografts by macrophages. However, the role of CD47 in solid organ transplantation remains undetermined. Here, we explored this question in mouse models of heart allotransplantation. We observed that the lack of CD47 in donor hearts had no deleterious effect on graft survival in syngeneic or single MHC class I-mismatched recipients, in which both wild-type (WT) and CD47 knockout (CD47 KO) mouse hearts survived long term with no sign of rejection. Paradoxically, elimination of donor CD47 was beneficial for graft survival in signal MHC class II- and class I- plus class II-mismatched combinations, in which CD47 KO donor hearts showed significantly improved survival compared to WT donor hearts. Similarly, CD47 KO donor hearts were more resistant than WT hearts to humoral rejection in α1,3-galactosyltransferase-deficient mice. Moreover, a significant prolongation of WT allografts was observed in recipient mice treated with antibodies against a CD47 ligand thrombospondin-1 (TSP1) or with TSP1 deficiency, indicating that TSP1-CD47 signaling may stimulate vascularized allograft rejection. Thus, unlike cellular transplantation, donor CD47 expression may accelerate the rejection of vascularized allografts.

Keywords: CD47; T cell; antibody; heart transplantation; macrophage.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allografts / immunology*
  • Animals
  • CD47 Antigen / genetics
  • CD47 Antigen / immunology*
  • Cell Transplantation / methods
  • Graft Rejection / genetics
  • Graft Rejection / immunology*
  • Graft Survival / genetics
  • Graft Survival / immunology*
  • Heart Transplantation / methods
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Thrombospondin 1 / genetics
  • Thrombospondin 1 / immunology*
  • Transplantation, Heterologous / methods
  • Transplantation, Homologous / methods

Substances

  • CD47 Antigen
  • Thrombospondin 1
  • Thbs1 protein, mouse