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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., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

CD47-SIRPα signaling plays an important role in regulating macrophage and dendritic cell (DC) activation. Here we investigated the role of CD47 expression on donor cells in tolerance induction by combined treatment with donor-specific transfusion (DST) plus anti-CD154 mAb in a mouse model of fully MHC-mismatched heart allotransplantation. The majority of BALB/c recipient mice that received anti-CD154 and CD47(+/+) B6 splenocytes (DST) showed indefinite donor heart survival (median survival time, MST > 150 days). Donor heart survival was improved in anti-CD154-treated BALB/c mice that received CD47(+/-) (MST = 90 days) or CD47(-/-) B6 DST (MST = 42 days) when compared to the nontreated (MST = 7 days) and anti-CD154 alone-treated (MST = 15 days) controls, but significantly reduced when compared to mice receiving anti-CD154 plus CD47(+/+) B6 DST. Recipient mice treated with anti-CD154 plus CD47(-/-) or CD47(+/-) DST also showed significantly increased antidonor, but not anti-third-party, MLR responses compared to those receiving anti-CD154 and CD47(+/+) DST. Furthermore, CD47(-/-) DST induced rapid activation of CD11c(hi)SIRPα(hi)CD8α(-) DCs via a mechanism independent of donor alloantigens. These results demonstrated that CD47 expression on donor cells is essential to the success of tolerance induction by combined therapy with DST and CD40/CD154 blockade.

Signal regulatory protein α (SIRPα) is a critical immune inhibitory receptor on macrophages, and its interaction with CD47 prevents autologous phagocytosis. We have previously shown that pig CD47 does not interact with human SIRPα, and that human CD47 expression inhibits phagocytosis of porcine cells by human macrophages in vitro. In this study, we have investigated the potential of human CD47 expression to promote porcine cell survival in vivo. Human CD47-expressing and control porcine B-lymphoma cells were transplanted into T- and B-cell-deficient nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice that express SIRPα capable of interacting with human CD47. Only the human CD47-expressing porcine lymphoma cells survived and were able to form tumors in NOD/SCID mice; however, both the control and human CD47-expressing porcine cells survived in macrophage-depleted NOD/SCID mice. These results indicate that transgenic expression of human CD47 may provide an effective approach to inhibiting macrophage-mediated xenograft rejection in clinical xenotransplantation.

CD47 is a ligand of the inhibitory receptor, signal regulatory protein (SIRP)alpha, and its interaction with SIRPalpha on macrophages prevents phagocytosis of autologous hematopoietic cells. CD47-SIRPalpha signaling also regulates dendritic cell (DC) endocytosis, activation, and maturation. In this study, we show that CD47 expression on donor cells plays an important role in suppression of allograft rejection by donor-specific transfusion (DST). DST was performed by i.v. injection of splenocytes from C57BL/6 donors into MHC class I-disparate bm1 mice 7 d prior to donor skin grafting. Administration of wild-type (WT) C57BL/6 donor splenocytes markedly prolonged donor skin survival in bm1 mouse recipients. In contrast, bm1 mice receiving DST from CD47 knockout (KO) donors showed no inhibition or even acceleration of donor skin graft rejection compared with non-DST control (naive) bm1 mice. T cells from bm1 mice receiving CD47 KO, but not WT, DST exhibited strong anti-donor responses. The ability of DST to suppress alloresponses was positively correlated with the density of CD47 molecules on donor cells, as CD47(+/-) DST was able to prolonged donor skin survival, but to a significantly less extent than WT DST. Furthermore, DCs from CD47 KO, but not WT, DST recipients showed rapid activation and contributed to donor skin rejection. These results show for the first time that CD47 on donor cells is required to repress recipient DC activation and suppress allograft rejection after DST, and suggest CD47 as a potential target for facilitating the induction of transplant tolerance.

Background: We have previously shown that the interspecies incompatibility of CD47 plays an important role in triggering rejection of xenogeneic hematopoietic cells by macrophages. However, it remains unknown whether CD47 incompatibility also contributes to the rejection of non-hematopoietic xenografts., Aims: Here, we investigated the role of CD47 in preventing macrophage-mediated rejection of thymic epithelial cells in a mouse model of thymic transplantation across the CD47 barrier., Methods: Wild-type (WT) and CD47 KO mice were thymectomized and treated with T cell-depleting mAbs, and implanted with fetal thymus from syngeneic WT or CD47 KO donors., Results: Transplantation of CD47 KO mouse thymus led to T cell recovery in thymectomized, T cell-depleted WT mice. Similar to the control WT mouse thymic grafts, CD47 KO mouse thymic grafts showed a normal distribution of thymocyte subsets, and almost all of the thymocytes were recipient origin. Furthermore, histological analysis confirmed long-term survival of CD47 KO mouse thymic epithelial cells in WT mouse recipients., Conclusions: These results demonstrate that, unlike hematopoietic cells, CD47 KO mouse thymus can survive and function in WT mice. Furthermore, our data implicate that the role of CD47 in xenograft rejection may differ for different types of xenografts, and that CD47 incompatibility is unlikely to impede thymic xenotransplantation, a potential approach to inducing xenotolerance, by triggering macrophage-mediated rejection.