Anti-major histocompatibility complex class II treatment prevents graft rejection in the hamster-to-rat cardiac xenograft

Background. Several groups have achieved graft acceptance in the concordant hamster to rat model by using a combination of anti-proliferative drugs an d conventional immunosuppressive therapy. However, such aggressive treatmen t often leads to the recipient dying with a functional xenograft, as a resu lt of opportunistic infections. This study aimed to investigate the effects of a short course of therapy with an anti-MHC class II monoclonal antibody treatment (chimeric OX6 [cOX6]) in combination with cyclosporin A (CyA) in a concordant hamster-to-rat xenograft model. Methods. Rats receiving hamster cardiac xenografts were given CyA or cOX6 a lone or in combination and were monitored daily to assess the effect of tre atment on graft survival. Additional studies monitored the effect of treatm ent on the production of cytolytic anti-hamster antibodies by the recipient and the deposition of immunoglobulin (Ig)M and complement factors within t he xenograft. Results. Treatment with CyA only had no effect on graft survival, whereas t reatment with cOX6 increased graft survival time by 2 days. The median graf t survival time for cOX6+CyA was 76 days. cOX6 treatment of rats having und ergone transplants inhibited the rise in cytotoxic anti-hamster antibodies in peripheral blood until day 5, whereas combination therapy completely inh ibited anti-hamster antibody formation. Fluorescence-activated cell sorter analysis showed treatment with cOX6 significantly reduced circulating B cel l numbers until day 5. Anti-MHC class II treatment also markedly reduced th e deposition of both IgM and C3. Anti-MHC class II treatment with CyA gives long term survival in concordant xenografts without severe side effects. Conclusions The mechanism of action of this combination is complex and coul d be caused by an initial inhibition of B cell function by the anti-MHC cla ss II treatment and the subsequent inhibition of T cell dependent pathways by CyA.