Prevention of renal allograft rejection in primates by blocking the B7/CD28 pathway

Background. There is accumulating evidence that blockade of the costimulato ry pathways offers a valid approach for immune suppression after solid orga n transplantation. In this study, the efficacy of anti-CD86 and anti-CD86 m onoclonal antibodies (mAbs) in combination with cyclosporine (CsA) to preve nt renal allograft rejection was tested in non-human primates. Methods. Rhesus monkeys were transplanted with a partly major histocompatib ility complex-matched kidney on day 0. Anti-CD80 and anti-CD86 mAbs were ad ministered intravenously daily for 14 days starting at day -1, CsA was give n intramuscularly for 35 days starting dust after transplantation, The kidn ey function was monitored by determining serum creatinine levels. Results, The combination of anti-CD80 and anti-CD86 mAbs completely abrogat ed the mixed lymphocyte reaction. Untreated rhesus monkeys rejected the kid ney allograft in 5-7 days. Treatment with anti-CD80 plus anti-CD86 mAbs res ulted in a significantly prolonged graft survival of 28 +/- 7 days (P = 0.0 25). There were no clinical signs of side effects or rejection during treat ment. Kidney graft rejection started after the antibody therapy was stopped . The anti mouse anti body response was delayed from day 10 to 30 after the first injection. No difference in,graft survival was observed between anim als treated with CsA alone or in combination with anti-CD80 and anti-CD86 m Abs. However, treatment with anti-CD80 and anti-CD86 mAbs reduced developme nt of vascular rejection. Conclusions. In combination, anti-CD80 and anti-CD86 mAbs abrogate T-cell p roliferation in vitro, delay the anti-mouse antibody response in vivo, and prevent graft rejection and development of graft vascular disease in a prec linical vascularized transplant model in non-human primates.