NEW AVENUES IN THE USE OF CYCLOSPORIN FOR TRANSPLANTATION. GRAFT AND DONOR PRETREATMENT

Abstract

Modification of graft immunogenicity using graft (GPTX) and donor pretreatment (DPTX) has been pursued in an attempt to modify allograft immunogenicity using various immunosuppressive agents. The murine skin allograft and canine renal allograft models were used to study the efficacy of Cyclosporine (Cy A) as a DPTX and GPTX prior to transplantation. Tail skin allografts from C3HHeN male mice were grafted to Balb/c female mouse recipients. Minimal immunosuppression was given to all skin graft recipients. Skin allograft were either GPTX with Cy A, DPTX with either Cy A, methylprednisolone (MP), or cyclophosphamide (CP), or Cy A GPTX and DPTX with the three drugs alone or in combination. Cy A GPTX alone of skin allografts did not significantly prolong survival. DPTX with Cy A significantly prolonged skin graft survival, however, CP or MP alone did not. The various combinations of MP, Cy A, and CP as DPTX and MP, Cy A, and CP DPTX used together with Cy A GPTX also significantly prolonged murine skin allograft survival. Kidney allografts used unrelated mongrel dogs as donors or recipients. Renal transplant experimental groups were either: Non-pretreated and immediately transplanted, nonpretreated and hypothermically stored (HS) for 24 hours in Collins (C-2) solution, GPTX with 12.5 mg Cy A during 24 hr. HS in C-2, DPTX (25 mg/kg), of Cy A DPTX (15 mg/kg) and GPTX during 24 hrs. Hs in C-2. Cy A GPTX during HS was sometimes effective in prolonging kidney allograft survival > 30 days using only minimal immunosuppression with azathioprine. Cy A DPTX prolonged survival somewhat, but not significantly. Improved results were seen, however, when Cy A DPTX was used together with Cy A graft pretreatment. These results indicate the potential for the successful use of Cy A as a donor and/or graft pretreatment, however, further studies will be necessary to optimize the use of Cy A in these modalities.