Identification of New Carbohydrate and Membrane Protein Antigens in Cardiac Xenotransplantation

Byrne, Guerard W.; Stalboerger, Paul G.; Du, Zeji; Davis, Tessa R.; McGregor, Christopher G.A.

doi:10.1097/tp.0b013e318203c27d

Cited by 104 publications

(94 citation statements)

References 30 publications

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“…Knockout of the galactosyltransferase enzyme (GalTKO) eliminates the carbohydrate antigen from porcine cells and was a key step to overcome hyperacute rejection of other organs (9–11). However, innate (mainly preformed antibody directed against other targets) and adaptive immune responses still persist in recipients of GalTKO organs and tissues (9, 12–15). The adaptive response to lung xenotransplants has not yet been studied since they have not yet reached a relevant duration of survival; accordingly, most lung xeno research has been focused towards early inflammation.…”

Section: Text Of Reviewmentioning

confidence: 99%

Lung xenotransplantation

Laird

Burdorf

Pierson

2016

Current Opinion in Organ Transplantation

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Purpose-To review recent progress in the field of lung xenotransplantation, including mechanisms of xenograft injury, and the influence of mechanism-directed genetic modifications and other interventions that may soon enable therapeutic use of pig lungs in humans.Recent findings-An extensive series of lung xenotransplantation experiments demonstrates that multiple genetic modifications targeting known xenogeneic lung injury mechanisms are associated with incremental improvements in lung survival or function. Addition of human complement (hCD46, hCD55), coagulation (hEPCR, hTBM, hTFPI, hCD39), or antiinflammatory pathway regulatory genes (HO-1, HLA-E), and GalT and Neu5Gc gene knockout has each demonstrated protective effects on lung survival or function. In addition, drug treatments targeting key inflammatory and clotting pathways have been shown to attenuate residual mechanisms of lung injury. Work with other pig organs in primate models show that regimens based on costimulatory pathway blocking antibodies prolong xenograft function for months to years, suggesting that once initial lung inflammation mechanisms are fully controlled, clinically useful application of pig lung xenografts may soon be feasible.Summary-Genetic modification of pigs coupled with drugs targeting complement activation, coagulation, and inflammation have significantly increased duration of pig lung function in ex vivo human blood perfusion models, and life supporting lung xenograft survival in vivo .

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Section: Text Of Reviewmentioning

confidence: 99%

Lung xenotransplantation

Laird

Burdorf

Pierson

2016

Current Opinion in Organ Transplantation

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“…Improvements have been made in nearly all aspects of the field except one, the availability of donor organs. Xenotransplantation could solve the organ shortage problem, but has been limited because of the antibody barrier posed by xenoantigens present on the surface of all pig organs (1, 2). …”

Section: Introductionmentioning

confidence: 99%

Reduced Binding of Human Antibodies to Cells From GGTA1/CMAH KO Pigs

Burlak

Paris

Lutz

et al. 2014

American Journal of Transplantation

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Xenotransplantation using genetically modified pig organs could solve the donor organ shortage problem. Two inactivated genes that make humans unique from pigs are GGTA1 and CMAH, the products of which produce the carbohydrate epitopes, aGal and Neu5Gc that attract preformed human antibody. When the GGTA1 and CMAH genes were deleted in pigs human antibody binding was reduced in preliminary analysis. We analyzed the binding of human IgM and IgG from 121 healthy human serum samples for binding to GGTA1 KO and GGTA1/CMAH KO peripheral blood mononuclear cells (PBMC). We analyzed a sub population for reactivity towards genetically modified pig PBMC as compared to chimpanzee and human PBMC. Deletion of the GGTA1 and CMAH genes in pigs improved the crossmatch results beyond those observed with chimpanzees. Sorting the 121 human samples tested against the GGTA1/CMAH KO pig PBMC did not reveal a distinguishing feature such as blood group, age or gender. Modification of genes to make pig carbohydrates more similar to humans has improved the cross match with human serum significantly.

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“…−/− pig endothelial cells with sera from primates that had rejected GGTA1 −/− pig hearts [24,25]. Expression of B4GALNT2 in human cells significantly increased antibodydependent complement-mediated lysis when these cells were challenged with serum from pig-to-baboon cardiac xenotransplantation sensitized recipient serum [25] while its deletion in pig PBMCs efficiently reduced human IgG and IgM binding and decreased human anti-porcine cytotoxicity [26,27].…”

Section: Modification Of Donor Pigs To Mitigate the Immunementioning

confidence: 99%

Gene Editing, Gene Therapy, and Cell Xenotransplantation: Cell Transplantation Across Species

Mourad

Gianello

2017

Curr Transpl Rep

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Purpose of Review Cell xenotransplantation has the potential to provide a safe, ethically acceptable, unlimited source for cell replacement therapies. This review focuses on genetic modification strategies aimed to overcome remaining hurdles standing in the way of clinical porcine islet transplantation and to develop neural cell xenotransplantation. Recent Findings In addition to previously described genetic modifications aimed to mitigate hyperacute rejection, instant blood-mediated inflammatory reaction, and cell-mediated rejection, new data showing the possibility of increasing porcine islet insulin secretion by transgenesis is an interesting addition to the array of genetically modified pigs available for xenotransplantation. Moreover, combining multiple modifications is possible today thanks to new, improved genomic editing tools. Summary Genetic modification of large animals, pigs in particular, has come a long way during the last decade. These modifications can help minimize immunological and physiological incompatibilities between porcine and human cells, thus allowing for better tolerance and function of xenocells.

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Identification of New Carbohydrate and Membrane Protein Antigens in Cardiac Xenotransplantation

Cited by 104 publications

References 30 publications

Lung xenotransplantation

Lung xenotransplantation

Reduced Binding of Human Antibodies to Cells From GGTA1/CMAH KO Pigs

Gene Editing, Gene Therapy, and Cell Xenotransplantation: Cell Transplantation Across Species

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