Induction of immune tolerance to a transplantation carbohydrate antigen by gene therapy with autologous lymphocytes transduced with adenovirus containing the corresponding gylcosyltransferase gene

Abstract

Induction of tolerance to transplantation carbohydrate antigens is of clinical significance in recipients of ABO-incompatible allografts, or of xenografts. The experimental animal model used for studying such tolerance was that of α1,3galactosyltransferase (α1,3GT) knockout (KO) mice, which lacks the α-gal epitope (Galα1-3Galβ1-4GlcNAc-R) and which can produce the anti-Gal antibody against it. In contrast, wild-type (WT) mice synthesize the α-gal epitope and are immunotolerant to it. KO lymphocytes transduced in vitro with adenovirus containing the α1,3GT gene (AdαGT) express α-gal epitopes. Administration of such lymphocytes into KO mice resulted in tolerization of naïve and memory anti-Gal B cells. Mice tolerized by AdαGT transduced lymphocytes failed to produce anti-Gal following immunizations with pig kidney membranes (PKM) expressing multiple α-gal epitopes. This tolerance was perpetuated by transplanted syngeneic WT mouse hearts expressing α-gal epitopes. Transplanted WT hearts survived in the tolerized KO mice for at least 100 days, despite repeated PKM immunizations. Control mice receiving lymphocytes transduced with adenovirus lacking the α1,3GT gene were not tolerized, but produced anti-Gal and rejected transplanted WT hearts. This study suggests that autologous lymphocytes transduced with adenovirus containing A or B transferase genes may induce a similar tolerance to blood group antigens in humans.