A LONG-TERM STUDY OF ALLOGENEIC RAT HINDLIMB TRANSPLANTS IMMUNOSUPPRESSED WITH RS-61443

Although technically possible, limb allotransplantation has not been a pplied clinically. The skin component is especially antigenic, requiri ng high immunosuppressant doses with an unacceptable toxicity profile. RS-61443, an experimental mycophenolic acid ester that inhibits lymph ocyte proliferation without major systemic toxicity, was tested as an immunosuppressant to prevent rejection of rat hindlimb allotransplants . Utilizing Brown-Norway donors and F344 recipients to provide a major mismatch at the MHC, midfemur orthotopic limb transfer was performed with microsurgical repair of femoral vessels and sciatic nerve. Four p rimary groups were studied: autografts (n=4); untreated allografts (n= 6); allograft receiving CsA 10 mg/kg for 20 days, then twice per week (n=6); and allografts receiving RS-61443 30 mg/kg/day (n=6). Skin and soft tissues were biopsied to assess rejection. Autografts had indefin ite limb survival, while untreated allografts had complete acute rejec tion within 10-12 days. Five of the six CsA rate developed delayed mil d-moderate acute rejection within 6 months. In contrast, 5 of the 6 RS -61443 rats had no rejection after at least 32 weeks, while the sixth rat developed only slight rejection on skin biopsy. All animals regain ed full sensation and partial functional return. RS-61443 is highly ef fective as a primary immunosuppressant for hindlimb allotransplantatio n. The disturbing moderate rejection observed in CsA animals, which wa s absent with RS-61443, may significantly hamper function of transplan ted limbs.