title: The pathobiology of pig-to-primate xenotransplantation: a historical review.
abstract: 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.
authors.affiliation: The Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: David K C
authors.initials: DK
authors.lastname: Cooper
authors.affiliation: The Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Mohamed B
authors.initials: MB
authors.lastname: Ezzelarab
authors.affiliation: The Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Hara
authors.affiliation: The Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Hayato
authors.initials: H
authors.lastname: Iwase
authors.affiliation: The Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Whayoung
authors.initials: W
authors.lastname: Lee
authors.affiliation: The Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Wijkstrom
authors.affiliation: Institute for Cellular Therapeutics, Allegheny-Singer Research Institute, Pittsburgh, PA, USA.
authors.forename: Rita
authors.initials: R
authors.lastname: Bottino
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology*; D006085:Graft Survival / Q000276:immunology*; D006801:Humans; D011323:Primates; D034421:Sus scrofa / Q000276:immunology*; D014183:Transplantation, Heterologous / Q000379:methods
keywords: Non-human primate; Pathobiology; Pig; Xenotransplantation; islets; organs