Induction of donor-specific tolerance in rat hind-limb allografts under antilymphocyte serum and cyclosporine A protocol.

Composite tissue allograft (CTA) transplantation became a clinical reality despite major side effects associated with the administration of chronic immunosuppression. Development of new treatment modalities eliminating life-long immunosuppression is essential for the future of CTA transplantation. In this study, combined use of cyclosporine A (CsA) and antilymphocyte serum (ALS) was tested for the potential to induce tolerance in the rat hind-limb allograft recipients across a major histocompatibility (MHC) barrier (Lewis-Brown-Norway [LBN, RT1(l+n)] to Lewis [LEW, RT1(l)] rats). Thirty transplantations were performed in 5 experimental groups. Animals received CsA and ALS 12 hours before surgery for 21 days thereafter. Although the allograft controls rejected their limbs at day 7 combined treatment of CsA and ALS resulted in indefinite survival (over 420 d) in all allograft recipients. Long-term survivors showed 35% to 42% of donor-specific chimerism in the peripheral blood. Clinical tolerance was confirmed by acceptance of the donor-specific skin grafts and immunocompetence was confirmed by rejection of the third-party grafts. Mixed lymphocyte reaction revealed suppressed response against donor-type antigens and increased response to third-party antigens. Donor-specific tolerance across MHC barrier was induced in CTA allografts under 21 days protocol of ALS/CsA.