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Alpha1,3-galactosyltransferase gene-knockout pigs for xenotransplantation: where do we go from here?
- Source :
-
Transplantation [Transplantation] 2007 Jul 15; Vol. 84 (1), pp. 1-7. - Publication Year :
- 2007
-
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.
- Subjects :
- Animals
Antibodies, Heterophile immunology
Antigens, Heterophile blood
Antigens, Heterophile immunology
Blood Coagulation
Humans
Immunosuppression Therapy
Primates immunology
Primates surgery
Swine immunology
Thrombosis etiology
Thrombosis prevention & control
Transplantation Tolerance
Animals, Genetically Modified
Galactosyltransferases genetics
Organ Transplantation adverse effects
Organ Transplantation trends
Swine genetics
Transplantation, Heterologous adverse effects
Transplantation, Heterologous immunology
Transplantation, Heterologous trends
Subjects
Details
- Language :
- English
- ISSN :
- 0041-1337
- Volume :
- 84
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Transplantation
- Publication Type :
- Academic Journal
- Accession number :
- 17627227
- Full Text :
- https://doi.org/10.1097/01.tp.0000260427.75804.f2