title: Alpha1,3-galactosyltransferase gene-knockout pigs for xenotransplantation: where do we go from here?
abstract: The ability to genetically engineer pigs that no longer express the Galalpha1,3Gal (Gal) oligosaccharide has been a significant step toward the clinical applicability of xenotransplantation. Using a chronic immunosuppressive regimen based on costimulatory blockade, hearts from these pigs have survived from 2 to 6 months in baboons. Graft failure was predominantly from the development of a thrombotic microangiopathy. Potential contributing factors include the presence of preformed anti-nonGal antibodies or the development of low levels of elicited antibodies to nonGal antigens, natural killer (NK) cell or macrophage activity, and inherent coagulation dysregulation between pigs and primates. The breeding of pigs transgenic for an "anticoagulant" gene, such as human tissue factor pathway inhibitor, hirudin, or CD39, or lacking the gene for the prothrombinase, fibrinogen-like protein-2, is anticipated to inhibit the change in the endothelium to a procoagulant state that takes place in the pig organ after transplantation. The identification of the targets for anti-nonGal antibodies and/or human macrophages might allow further genetic modification of the pig, and xenogeneic NK cell recognition and activation may be inhibited by the transgenic expression of human leukocyte antigen molecules and/or by blocking the function of activating NK receptors. The ultimate goal of induction of T-cell tolerance may be possible only if these hurdles in the coagulation system and innate immunity can be overcome.
authors.affiliation: The Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA. cooperdk@upmc.edu
authors.forename: David K C
authors.initials: DK
authors.lastname: Cooper
authors.forename: Anthony
authors.initials: A
authors.lastname: Dorling
authors.forename: Richard N
authors.initials: RN
authors.lastname: Pierson
authors.forename: Michael
authors.initials: M
authors.lastname: Rees
authors.forename: Jorg
authors.initials: J
authors.lastname: Seebach
authors.forename: Mark
authors.initials: M
authors.lastname: Yazer
authors.forename: Hideki
authors.initials: H
authors.lastname: Ohdan
authors.forename: Michel
authors.initials: M
authors.lastname: Awwad
authors.forename: David
authors.initials: D
authors.lastname: Ayares
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000910:Antibodies, Heterophile / Q000276:immunology; D015478:Antigens, Heterophile / Q000097:blood / Q000276:immunology; D001777:Blood Coagulation; D005700:Galactosyltransferases / Q000235:genetics*; D006801:Humans; D007165:Immunosuppression Therapy; D016377:Organ Transplantation / Q000009:adverse effects / Q000639:trends; D011323:Primates / Q000276:immunology / Q000601:surgery; D013552:Swine / Q000235:genetics* / Q000276:immunology; D013927:Thrombosis / Q000209:etiology / Q000517:prevention & control; D023001:Transplantation Tolerance; D014183:Transplantation, Heterologous / Q000009:adverse effects / Q000276:immunology / Q000639:trends
chemical_list: D000910:Antibodies, Heterophile; D015478:Antigens, Heterophile; D005700:Galactosyltransferases; C045097:UDP-galactose-lactosylceramide alpha 1-4-galactosyltransferase