Role of Human CD200 Overexpression in Pig-to-Human Xenogeneic Immune Response Compared With Human CD47 Overexpression

Yan, Jing; Koo, Tai Yeon; Lee, Han Sin; Lee, Wook Bin; Kang, Byung Hee; Lee, Jae Ghi; Jang, Jinho; Fang, Taishi; Ryu, Jung Hwa; Ahn, Curie; Kim, Sung Joo; Yang, Jaeseok

doi:10.1097/tp.0000000000001966

Cited by 26 publications

(29 citation statements)

References 29 publications

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Section: Expression Of Hcd47mentioning

confidence: 99%

“…In vitro, expression of hCD47 on pig cells not only suppresses the activation of human macrophages but, importantly, also suppresses inflammatory cytokine (TNF‐α, IL‐1β, IL‐6) production, and macrophage‐mediated pig cell cytotoxicity . In addition, Yan et al have demonstrated that pig graft infiltration by human T cells is suppressed by expression of hCD47 . Illustrating the complex interaction of the immune, coagulation, and inflammatory systems, when hCD47 was expressed with human tissue factor pathway inhibitor (hTFPI), hCD47‐SIRP‐α signaling was potentiated …”

Section: Expression Of Hcd47mentioning

confidence: 99%

“…95,96 In addition, Yan et al have demonstrated that pig graft infiltration by human T cells is suppressed by expression of hCD47. 96 Illustrating the complex interaction of the immune, coagulation, and inflammatory systems, when hCD47 was expressed with human tissue factor pathway inhibitor (hTFPI), hCD47-SIRP-α signaling was potentiated. 95 In vivo evidence of the beneficial effect of expression of hCD47 in pigs has also been demonstrated but, like hHO-1, it has usually been expressed in pigs in combination with several other human transgenes, making it difficult to determine its individual effect.…”

Section: Transfection Of Cells With the Gene For Cd47 From The Same Smentioning

confidence: 99%

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Justification of specific genetic modifications in pigs for clinical organ xenotransplantation

Cooper

Hara

Iwase

et al. 2019

Xenotransplantation

129

131

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Xenotransplantation research has made considerable progress in recent years, largely through the increasing availability of pigs with multiple genetic modifications. We suggest that a pig with nine genetic modifications (ie, currently available) will provide organs (initially kidneys and hearts) that would function for a clinically valuable period of time, for example, >12 months, after transplantation into patients with end‐stage organ failure. The national regulatory authorities, however, will likely require evidence, based on in vitro and/or in vivo experimental data, to justify the inclusion of each individual genetic modification in the pig. We provide data both from our own experience and that of others on the advantages of pigs in which (a) all three known carbohydrate xenoantigens have been deleted (triple‐knockout pigs), (b) two human complement‐regulatory proteins (CD46, CD55) and two human coagulation‐regulatory proteins (thrombomodulin, endothelial cell protein C receptor) are expressed, (c) the anti‐apoptotic and “anti‐inflammatory” molecule, human hemeoxygenase‐1 is expressed, and (d) human CD47 is expressed to suppress elements of the macrophage and T‐cell responses. Although many alternative genetic modifications could be made to an organ‐source pig, we suggest that the genetic manipulations we identify above will all contribute to the success of the initial clinical pig kidney or heart transplants, and that the beneficial contribution of each individual manipulation is supported by considerable experimental evidence.

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Section: Expression Of Hcd47mentioning

confidence: 99%

Section: Expression Of Hcd47mentioning

confidence: 99%

Section: Transfection Of Cells With the Gene For Cd47 From The Same Smentioning

confidence: 99%

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Justification of specific genetic modifications in pigs for clinical organ xenotransplantation

Cooper

Hara

Iwase

et al. 2019

Xenotransplantation

129

131

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“…In vitro, porcine cells expressing hCD47 can reduce their phagocytosis by human macrophages (62). Moreover, the expression of hCD47 in porcine endothelial cells not only suppressed macrophage-mediated cytotoxic activity and inflammatory cytokine (TNF-α, IL-1β, IL-6) production but also inhibited human T-cell infiltration (133). In vivo, hCD47 expression increased xenogeneic hematopoietic engraftment chimerism in the murine model (102) and prolonged the survival porcine skin grafts in baboons (134).…”

Section: Inhibition Of Cellular Xenograft Rejectionmentioning

confidence: 99%

Xenotransplantation: Current Status in Preclinical Research

et al. 2020

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“…Results found in one study showed that porcine CD47 was able to bind to human SIRPA in vitro, while another showed that phagocytic inhibition was not induced between human macrophages and pig cells . Expression of human CD47 on porcine cells was required to inhibit phagocytosis by human macrophages . Together, these studies show evidence that human SIRPA and pig CD47 can bind, although binding is not sufficient for phagocytic inhibition.…”

Section: Introductionmentioning

confidence: 96%

Porcine signal regulatory protein alpha binds to human CD47 to inhibit phagocytosis: Implications for human hematopoietic stem cell transplantation into severe combined immunodeficient pigs

Boettcher

Cunnick

Powell

et al. 2018

Xenotransplantation

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Background: Severe combined immunodeficient (SCID) pigs are an emerging animal model being developed for biomedical and regenerative medicine research. SCID pigs can successfully engraft human-induced pluripotent stem cells and cancer cell lines. The development of a humanized SCID pig through xenotransplantation of human hematopoietic stem cells (HSCs) would be a further demonstration of the value of such a large animal SCID model. Xenotransplantation success with HSCs into non-obese diabetic (NOD)-derived SCID mice is dependent on the ability of NOD mouse signal regulatory protein alpha (SIRPA) to bind human CD47, inducing higher phagocytic tolerance than other mouse strains. Therefore, we investigated whether porcine SIRPA binds human CD47 in the context of developing a humanized SCID pig.Methods: Peripheral blood mononuclear cells (PBMCs) were collected from SCID and non-SCID pigs. Flow cytometry was used to assess whether porcine monocytes could bind to human CD47. Porcine monocytes were isolated from PBMCs and were subjected to phagocytosis assays with pig, human, and mouse red blood cell (RBC) targets. Blocking phagocytosis assays were performed by incubating human RBCs with anti-human CD47 blocking antibody B6H12, non-blocking antibody 2D3, and nonspecific IgG1 antibody and exposing to human or porcine monocytes. Results:We found that porcine SIRPA binds to human CD47 in vitro by flow cytometric assays. Additionally, phagocytosis assays were performed, and we found that porcine monocytes phagocytose human and porcine RBCs at significantly lower levels than mouse RBCs. When human RBCs were preincubated with CD47 antibodies B6H12 or 2D3, phagocytosis was induced only after B6H12 incubation, indicating the lower phagocytic activity of porcine monocytes with human cells requires interaction between porcine SIRPA and human CD47. AUTH O R CO NTR I B UTI O N S ANB designed and performed experiments, analyzed data, and wrote the manuscript; JEC, CLL, EJP, and TKE designed experiments, reviewed data, and edited manuscript; EJP performed statistical analysis; SEC genotyped piglets, managed SCID pig colony, and helped with sample collection; and CKT designed experiments, reviewed data, and edited manuscript. O RCI D Adeline N. Boettcher

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Role of Human CD200 Overexpression in Pig-to-Human Xenogeneic Immune Response Compared With Human CD47 Overexpression

Abstract: Therefore, overexpression of human CD200 in donor pigs could constitute a promising strategy for overcoming xenograft rejection.

Cited by 26 publications

References 29 publications

Justification of specific genetic modifications in pigs for clinical organ xenotransplantation

Justification of specific genetic modifications in pigs for clinical organ xenotransplantation

Xenotransplantation: Current Status in Preclinical Research

Porcine signal regulatory protein alpha binds to human CD47 to inhibit phagocytosis: Implications for human hematopoietic stem cell transplantation into severe combined immunodeficient pigs

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