cyclophosphamide plus Busulfan-induced tolerance in rat into mouse xenotransplantation

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We have recently reported a new method of cyclophosphamide(CP) plus Busulfan (BU)-induced tolerance. Recently, we could established a modified method to induce both permanent mixed chimerism and skin allograft tolerance in H-2 mismatched combinations (J Immunol 2000; 164: 34). Our present protocol consists on injection of 1 x 10^8 allogeneic spleen cells (SC) on day 0, and administration of 200mg/kg CP and 30mg/kg BU on day 2 followed by 1 x 10^7 T cell-depleted donor bone marrow cells (BMC) on day 3. As a consequence, we also found that the correlation between the establishment of mixed chimerism and skin allograft tolerance and the clonal destruction as the major mechanisms of tolerance induction. In the present study, we applied our new system to rat into mouse xenograft tolerance. Mixed chimerism was detectable (5-20%) at 2-8 weeks after treatments, and F344 rat skins were significantly and specifically prolonged (median 40 days, max 75 days). However, neither permanent mixed chimerism nor skin xenograft tolerance could not be induced. NK cell-depletion did not permit more profound degree of mixed chimerism or induce more skin graft prolongation.. The present study indicated that our new protocol can induce temporal mixed chimerism and moderate skin graft polongation in a donor specific manner.