Donor CD47 controls T cell alloresponses and is required for tolerance induction following hepatocyte allotransplantation

Zhang, Mingyou; Wang, Hui; Tan, Shulian; Navarro-Alvarez, Nalú; Zheng, Yang; Yang, Yong‐Guang

doi:10.1038/srep26839

Cited by 21 publications

(26 citation statements)

References 30 publications

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“…Previously, we have demonstrated that HLA class I‐silenced cells have a superior capacity to escape antibody‐mediated, complement‐dependent and cellular‐dependent cytotoxicity in vitro and in vivo . Moreover, recent studies have shown that CD8 + T cells play an important role in cellular alloimmune responses against the transplanted hepatocytes . The decrease in proliferation observed in our MHLC, when HLA class I expression was down‐regulated, may indicate a lower activation of both CD4 + and CD8 + T cells.…”

Section: Discussionmentioning

confidence: 87%

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Silencing of HLA class I on primary human hepatocytes as a novel strategy for reduction in alloreactivity

Figueiredo

Oldhafer

Wittauer

et al. 2019

J Cellular Molecular Medi

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In contrast to the whole liver, primary hepatocytes are highly immunogenic. Thus, alternative strategies of immunomodulation after hepatocyte transplantation are of special interest. Silencing of HLA class I expression is expected to reduce the strength of allogeneic immune responses and to improve graft survival. In this study, primary human hepatocytes (PHH) were isolated using a two‐step‐collagenase perfusion‐technique and co‐cultured with allogeneic lymphocytes in terms of a mixed lymphocyte hepatocyte culture. Expression of HLA class I on PHH was silenced using lentiviral vectors encoding for β2‐microglobulin‐specific short hairpin RNA (shβ2m) or non‐specific shRNA (shNS) as control. The delivery of shβ2m into PHH caused a decrease by up to 96% in β2m transcript levels and a down‐regulation of HLA class I cell surface expression on PHH by up to 57%. Proliferative T cell alloresponses against HLA‐silenced PHH were significantly lower than those observed form fully HLA‐expressing PHH. In addition, significantly lower secretion of pro‐inflammatory cytokines was observed. Levels of albumin, urea and aspartate‐aminotransferase did not differ in supernatants of cultured PHH. In conclusion, silencing HLA class I expression on PHH might represent a promising approach for immunomodulation in the transplant setting without compromising metabolic function of silenced hepatocytes.

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Section: Discussionmentioning

confidence: 87%

“…9,10,19 Moreover, recent studies have shown that CD8 + T cells play an important role in cellular alloimmune responses against the transplanted hepatocytes. 20,21 The decrease in proliferation observed in our MHLC, when HLA class I expression was down-regulated, may indicate a lower activation of both CD4 + and CD8 + T cells.…”

Section: Discussionmentioning

confidence: 91%

Silencing of HLA class I on primary human hepatocytes as a novel strategy for reduction in alloreactivity

Figueiredo

Oldhafer

Wittauer

et al. 2019

J Cellular Molecular Medi

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“…Previous studies revealed that MDSC were required for the tolerance induction of hepatocyte transplantation and that CD47-deficient hepatocytes could not be tolerated and paradoxically stimulated antidonor T cell responses. 41 Here, we report that the SIRPα/CD47 pathway is crucial for the induction and the maintenance of established immune tolerance to kidney allograft and to prevent allograft rejection associated with increased macrophage infiltrates. We also describe that interrup- We also observed in vivo that administration of anti-SIRPα or anti-CD47 mAbs induced a decrease of MDSC in the blood of naïve or tolerant animals whereas total myeloid cells (expressing SIRPα as well) remained stable in leukocytes excluding any direct cytotoxicity of these mAbs.…”

Section: Discussionmentioning

confidence: 93%

SIRPα/CD47 axis controls the maintenance of transplant tolerance sustained by myeloid-derived suppressor cells

Pengam

Durand

Usal

et al. 2019

American Journal of Transplantation

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Myeloid‐derived suppressor cells (MDSC) are a heterogeneous population of immature hematopoietic precursors known to suppress immune responses. Interaction of SIRP alpha (SIRPα), expressed by myeloid cells, with the ubiquitous receptor CD47 is an important immune checkpoint of the innate response regulating macrophages and dendritic cells functions. We previously described that MDSC expressing SIRPα accumulated after transplantation and maintained kidney allograft tolerance. However, the role of the SIRPα/CD47 axis on MDSC function remained unknown. Here, we found that blocking SIRPα or CD47 with monoclonal antibodies (mAbs) induced differentiation of MDSC into myeloid cells overexpressing MHC class II, CD86 costimulatory molecule and increased secretion of macrophage‐recruiting chemokines (eg, MCP‐1). Using a model of long‐term kidney allograft tolerance sustained by MDSC, we observed that administration of blocking anti‐SIRPα or CD47 mAbs induced graft dysfunction and rejection. Loss of tolerance came along with significant decrease of MDSC and increase in MCP‐1 concentration in the periphery. Graft histological and transcriptomic analyses revealed an inflammatory (M1) macrophagic signature at rejection associated with overexpression of MCP‐1 mRNA and protein in the graft. These findings indicate that the SIRPα‐CD47 axis regulates the immature phenotype and chemokine secretion of MDSC and contributes to the induction and the active maintenance of peripheral acquired immune tolerance.

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“…Researchers investigating the role of CD47, a member of the Ig superfamily which provides a protective signal against phagocytotic activity of macrophages, recently reported on the contribution of donor CD47 in the regulation of T-cell alloresponses in hepatocyte transplantation. Thru a collection of innovative experiments, they were able to show the important role that CD47 plays in the control of not only T-cell alloresponses but also tolerance induction following HT (97). This work, combined with other published works, adds to the building evidence that CD47 incompatibility may induce both innate and adaptive immune mediated rejection of transplanted hepatocytes (97–101).…”

Section: Improving Transplanted Hepatocyte Survival and Monitoringmentioning

confidence: 99%

“…Thru a collection of innovative experiments, they were able to show the important role that CD47 plays in the control of not only T-cell alloresponses but also tolerance induction following HT (97). This work, combined with other published works, adds to the building evidence that CD47 incompatibility may induce both innate and adaptive immune mediated rejection of transplanted hepatocytes (97–101). …”

Section: Improving Transplanted Hepatocyte Survival and Monitoringmentioning

confidence: 99%

Clinical Hepatocyte Transplantation: What Is Next?

et al. 2017

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Purpose of review Significant recent scientific developments have occurred in the field of liver repopulation and regeneration. While techniques to facilitate liver repopulation with donor hepatocytes and different cell sources have been studied extensively in the laboratory, in recent years clinical hepatocyte transplantation (HT) and liver repopulation trials have demonstrated new disease indications and also immunological challenges that will require the incorporation of a fresh look and new experimental approaches. Recent findings Growth advantage and regenerative stimulus are necessary to allow donor hepatocytes to proliferate. Current research efforts focus on mechanisms of donor hepatocyte expansion in response to liver injury/preconditioning. Moreover, latest clinical evidence shows that important obstacles to HT include optimizing engraftment and limited duration of effectiveness, with hepatocytes being lost to immunological rejection. We will discuss alternatives for cellular rejection monitoring, as well as new modalities to follow cellular graft function and near-to-clinical cell sources. Summary HT partially corrects genetic disorders for a limited period of time and has been associated with reversal of ALF. The main identified obstacles that remain to make HT a curative approach include improving engraftment rates, and methods for monitoring cellular graft function and rejection. This review aims to discuss current state-of-the-art in clinical HT and provide insights into innovative approaches taken to overcome these obstacles.

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Donor CD47 controls T cell alloresponses and is required for tolerance induction following hepatocyte allotransplantation

Cited by 21 publications

References 30 publications

Silencing of HLA class I on primary human hepatocytes as a novel strategy for reduction in alloreactivity

Silencing of HLA class I on primary human hepatocytes as a novel strategy for reduction in alloreactivity

SIRPα/CD47 axis controls the maintenance of transplant tolerance sustained by myeloid-derived suppressor cells

Clinical Hepatocyte Transplantation: What Is Next?

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