Update: cardiac xenotransplantation.
OBJECTIVE
To review the latest development in cardiac xenotransplantation in small and large animal models and related in-vitro studies.


RESULTS
With the recent introduction of alpha1,3-galactosyltransferase gene-knockout (GT-KO) pig organs for xenotransplantation, improved cardiac graft survival has been obtained. However, this experience has demonstrated the importance of pig antigens other than Galalpha1,3Gal (Gal) antigens (so-called nonGal antigens) as targets for primate anti-pig antibodies. Several in-vitro studies have confirmed that, although the incidence and levels of anti-nonGal antibodies in nonhuman primates and humans are significantly less when compared with total anti-pig antibodies (i.e., anti-Gal + anti-nonGal), they can result in complement-mediated lysis of GT-KO pig cells. More recently, it has been demonstrated that regulatory T cells suppress the cellular xenogeneic response, thus potentially preventing or reducing T-cell-mediated rejection. The importance of thrombotic microangiopathy as a feature of the immune/inflammatory response and incompatibilities between the coagulation-anticoagulation systems of pig and primate are receiving increasing attention. Development of GT-KO pigs transgenic for one or more 'antithrombotic' genes, for example, CD39 or tissue factor pathway inhibitor, may contribute to overcoming these problems.


CONCLUSIONS
Although GT-KO pigs have provided an advance over wild-type pigs as a source of organs for transplantation into primates, further genetic modification of GT-KO pigs is required to overcome the remaining immune barriers before a clinical trial of cardiac xenotransplantation can be contemplated.
Ekser
Burcin
B
Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15261, USA.
Cooper
David Kc
DK
D000818:Animals; D030801:Animals, Genetically Modified; D000906:Antibodies / Q000097:blood; D001777:Blood Coagulation; D017690:Cell Transplantation; D003167:Complement Activation; D005700:Galactosyltransferases / Q000172:deficiency / Q000235:genetics; D055786:Gene Knockout Techniques; D006084:Graft Rejection / Q000097:blood / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival; D016027:Heart Transplantation; D006801:Humans; D013552:Swine; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014183:Transplantation, Heterologous
D000906:Antibodies; D005700:Galactosyltransferases; C530267:alpha-1,3-galactosyltransferase 1, porcine