Skin Allograft Acceptance with Anti-CD154 in a Non-Human Primate Model

摘要

Traditional burn wound management involves application of topical antimicrobial agents with frequent dressing changes for superficial partial thickness burns and early excision and grafting of deep partial or full thickness burns. Combat related injuries tend to affect large areas and treatment has been often limited to split-thickness skin autografts. This approach has been limited by its requirement for an autologous donor graft sites. Allogenic skin transplantation would alleviate many of these problems, but has remained impractical due to graft rejection. To date, no clinically available intervention has been reported to induce long-term primary skin graft survival. However, murine models utilizing either costimulation blockade or costimulatory blockade together with donor specific transfusions (DST) have met with limited success. Previously we have used a humanized monoclonal antibody (hu5C8) directed against CD154 to induce longterm graft survival in a primate renal allograft model without the use of DST. In this work, we have applied these regimens with the addition of DST to a primary skin transplant model. Ten animals were transplanted with full thickness skin allografts mismatched at both class I and class II major histocompatibility loci. Of these, two were given no treatment, five were treated with anti-CD154 mAb alone, and three received anti-CD154 mAb combined with whole blood DST. All recipients also received autografts. Treatment with both hu5C8 alone and hu5C8 plus DST greatly prolonged allograft survival with mean survival time in the monotherapy group of > 226 days and mean survival time in the DST group of > 263 days. These results suggest that costimulation blockade with anti-cd154 can attenuate acute rejection of skin allografts and may lead to long-term survival of these grafts without chronic immunosuppression.