Suppression of human macrophage-mediated cytotoxicity by transgenic swine endothelial cell expression of HLA-G

Esquivel, Emilio; Maeda, Akira; Eguchi, Hiroshi; Asada, Mayumi; Sugiyama, Miku; Manabe, Chieko; Sakai, Rieko; Matsuura, Ryohei; Nakahata, Kengo; Okuyama, Hiroomi; Miyagawa, Shuji

doi:10.1016/j.trim.2014.12.004

Cited by 43 publications

(26 citation statements)

References 27 publications

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“…Natural killer cells have been demonstrated to participate in the cellular response to a pig graft [160][161][162][163][164] (although this has been difficult to detect in vivo), and transgenic expression of human leukocyte antigen (HLA)-G and/or E and/or Cw3 may inhibit their response [165][166][167][168][169][170][171]. Pigs expressing HLA-E of HLA-G have been produced, but not yet fully tested when on the preferable GTKO/ human complement-regulatory protein background [172][173][174]. Studies by Miyagawa's group indicate that expression of these transgenes may also inhibit macrophage activity, which is likely to be important after organ, islet, and cell transplantation [173,174].…”

Section: Natural Killer (Nk) Cellsmentioning

confidence: 99%

“…Pigs expressing HLA-E of HLA-G have been produced, but not yet fully tested when on the preferable GTKO/ human complement-regulatory protein background [172][173][174]. Studies by Miyagawa's group indicate that expression of these transgenes may also inhibit macrophage activity, which is likely to be important after organ, islet, and cell transplantation [173,174].…”

Section: Natural Killer (Nk) Cellsmentioning

confidence: 99%

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The pathobiology of pig‐to‐primate xenotransplantation: a historical review

Cooper

Ezzelarab

Hara

et al. 2016

Xenotransplantation

126

129

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The immunologic barriers to successful xenotransplantation are related to the presence of natural anti-pig antibodies in humans and non-human primates that bind to antigens expressed on the transplanted pig organ (the most important of which is galactose-α1,3-galactose [Gal]), and activate the complement cascade, which results in rapid destruction of the graft, a process known as hyperacute rejection. High levels of elicited anti-pig IgG may develop if the adaptive immune response is not prevented by adequate immunosuppressive therapy, resulting in activation and injury of the vascular endothelium. The transplantation of organs and cells from pigs that do not express the important Gal antigen (α1,3-galactosyltransferase gene-knockout [GTKO] pigs) and express one or more human complement-regulatory proteins (hCRP, e.g., CD46, CD55), when combined with an effective costimulation blockade-based immunosuppressive regimen, prevents early antibody-mediated and cellular rejection. However, low levels of anti-non-Gal antibody and innate immune cells and/or platelets may initiate the development of a thrombotic microangiopathy in the graft that may be associated with a consumptive coagulopathy in the recipient. This pathogenic process is accentuated by the dysregulation of the coagulation-anticoagulation systems between pigs and primates. The expression in GTKO/hCRP pigs of a human coagulation-regulatory protein, for example, thrombomodulin, is increasingly being associated with prolonged pig graft survival in non-human primates. Initial clinical trials of islet and corneal xenotransplantation are already underway, and trials of pig kidney or heart transplantation are anticipated within the next few years.

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Section: Natural Killer (Nk) Cellsmentioning

confidence: 99%

Section: Natural Killer (Nk) Cellsmentioning

confidence: 99%

The pathobiology of pig‐to‐primate xenotransplantation: a historical review

Cooper

Ezzelarab

Hara

et al. 2016

Xenotransplantation

126

129

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“…38 The collaborative interaction between NK cells and macrophages not only plays a significant role in xenograft rejection, even in the absence of T cells or xenoantibodies, 45,46 but also augments adaptive immune responses against xenoantigens in murine models. 35,46 In our experiments, CD8+ T-cell infiltration into islet xenografts was observed on the examination of liver biopsy specimens obtained from recipients after graft failure as previously reported, 9 porcine islets expressing human leukocyte antigen G and/or E [49][50][51] or steroid therapy in the event of unexplained, sustained D-dimer elevation (to reduce inflammatory cytokine production and tissue factor expression 52 ), in addition to IS targeting adaptive immune responses could address this issue.…”

Section: Discussionmentioning

confidence: 67%

D‐dimer level, in association with humoral responses, negatively correlates with survival of porcine islet grafts in non‐human primates with immunosuppression

Kang

Lee

Park

et al. 2017

Xenotransplantation

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“…Several groups have demonstrated that transgenic expression of human leukocyte antigen (HLA)-E and/or G in the ‘donor’ pig organ inhibits the NK cell response [18]. More recently, studies by Miyagawa's group indicate that expression of these transgenes may also inhibit macrophage activity, which is likely to be important after organ, islet, and cell transplantation [19,20]. …”

Section: Pig-to-primate Organ Transplantationmentioning

confidence: 99%

Recent advances in understanding xenotransplantation: implications for the clinic

Cooper

Bottino

2015

Expert Review of Clinical Immunology

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Summary The results of organ and cell allotransplantation continue to improve, but the field remains limited by a lack of deceased donor organs. Xenotransplantation, e.g., between pig and human, offers unlimited organs and cells for clinical transplantation. The immune barriers include a strong innate immune response in addition to the adaptive T cell response. The innate response has largely been overcome by the transplantation of organs from pigs with genetic modifications that protect their tissues from this response. T cell-mediated rejection can be controlled by immunosuppressive agents that inhibit costimulation. Coagulation dysfunction between the pig and primate remains problematic but is being overcome by the transplantation of organs from pigs that express human coagulation-regulatory proteins. The remaining barriers will be resolved by the introduction of novel genetically-engineered pigs. Limited clinical trials of pig islet and corneal transplantation are already underway.

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Suppression of human macrophage-mediated cytotoxicity by transgenic swine endothelial cell expression of HLA-G

Cited by 43 publications

References 27 publications

The pathobiology of pig‐to‐primate xenotransplantation: a historical review

The pathobiology of pig‐to‐primate xenotransplantation: a historical review

D‐dimer level, in association with humoral responses, negatively correlates with survival of porcine islet grafts in non‐human primates with immunosuppression

Recent advances in understanding xenotransplantation: implications for the clinic

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