This study was designed to investigate the effectiveness of combined perioperative anti-CD4 and human (h)CTLA4Ig therapy in preventing allorejection of small bowel transplantation in high-responder Lewis rat recipients of ACI grafts. Anti-CD4 (5 mg/kg x 4 days) or hCTLA4Ig (0.5 mg/rat x 2 days) therapy alone delayed, but did not prevent, allograft rejection after small bowel transplantation of ACI into Lewis rats. All grafts were rejected in 18 and 10 days, respectively. However, a regimen of anti-CD4 (5 mg/kg x 4 days) combined with hCTLA4Ig (0.5 mg/rat x 2 days) allowed indefinite survival of ACI small bowel allografts. Second donor-matched heart grafts were permanently accepted, whereas third-party (Sprague-Dawley) heart allografts were rejected by the tolerant recipients. These data suggest that these two reagents produced a synergistic effect in preventing allorejection of small bowel transplantation.

Induction of tolerance to transplantation carbohydrate antigens is of clinical significance in recipients of ABOincompatible allografts, or of xenografts. The experimental animal model used for studying such tolerance was that of a1,3galactosyltransferase (a1,3GT) knockout (KO) mice, which lacks the a-gal epitope (Gala1-3Galb1-4GlcNAc-R) and which can produce the anti-Gal antibody against it. In contrast, wild-type (WT) mice synthesize the a-gal epitope and are immunotolerant to it. KO lymphocytes transduced in vitro with adenovirus containing the a1,3GT gene (AdaGT) express a-gal epitopes. Administration of such lymphocytes into KO mice resulted in tolerization of naïve and memory anti-Gal B cells. Mice tolerized by AdaGT transduced lymphocytes failed to produce anti-Gal following immunizations with pig kidney membranes (PKM) expressing multiple a-gal epitopes. This tolerance was perpetuated by transplanted syngeneic WT mouse hearts expressing a-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 a1,3GT 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.

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