It has been difficult to induce donor-specific transplantation tolerance in high responder Lewis rats. Results presented below demonstrate that amounts of pretransplant anti-CD4 sufficient to allow allograft tolerance in low responder strains (5 mg/kg x 4 days) did not prevent the acute rejection of ACI heart allografts in high responder Lewis recipients. Higher doses of pretransplant anti-CD4 (10 mg/kg, 15 mg/kg, and 20 mg/kg) given alone could delay but not prevent allograft rejection. Pretransplant anti-CD4 combined with anti-CD8, thymectomy, and total lymphoid irradiation all failed to produce tolerance to ACI heart allografts. However, a regimen of anti-CD4 combined with CTLA4Ig allowed indefinite survival of ACI heart allografts (mean survival time, > 100 day). Second-donor matched heart grafts were permanently accepted, and third-party heart grafts were permanently accepted, and third-party heart allografts were rejected by the tolerant recipients. These results suggest a new combination therapeutic strategy for clinical transplantation.
[Show abstract][Hide abstract] ABSTRACT: 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.
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