The effects of combined treatment with the novel vitamin D analogue MC 1288 and cyclosporine A on cardiac allograft survival.
The efficacy of combined treatment with the novel vitamin D analogue MC 1288 (20-epi-1 alpha,25-dihydroxycholecalciferol) and cyclosporine A (CyA) in preventing rejection following organ transplantation was evaluated in the heterotopic cardiac allograft model. Wistar/Kyoto rats received hearts from PVG donors and were subsequently treated with MC 1288 and CyA in various dose combinations. Administration of MC 1288 0.1 microgram/kg together with CyA 5 mg/kg produced significantly prolonged graft survival times as compared with single therapy with MC 1288 0.1 microgram/kg (p < 0.01) or CyA 5 mg/kg (p < 0.001). MC 1288 and CyA were tested also in combination with the immunomodulating drug LS-2616, which, in several laboratories, is used as a model for the evaluation of new combinations of immunosuppressive drugs. LS-2616 abolishes the immunosuppressive effect of CyA and the transplanted hearts are thus rejected at the same time as grafts of untreated recipients, i.e. on day 8. The immunosuppressive effect of MC 1288 is also counteracted by LS-2616, but the effect is not absolute and the median graft survival time is 11.0 days. Combined treatment with MC 1288 and CyA in the presence of LS-2616 resulted in a median graft survival time of 14.0 days. The results obtained in our experiments indicate at least an additive effect of MC 1288 and CyA thus suggesting that in the future MC 1288, or other vitamin D analogues, might be used to control rejection, either alone, in combination with CyA or in combination with other immunosuppressive drugs with other mechanisms of action.
Johnsson
C
C
Department of Transplantation Surgery, University Hospital, Uppsala, Sweden.
Binderup
L
L
Tufveson
G
G
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D002117:Calcitriol / Q000627:therapeutic use*; D002118:Calcium / Q000097:blood; D016572:Cyclosporine / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D006085:Graft Survival / Q000187:drug effects*; D016027:Heart Transplantation; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D006912:Hydroxyquinolines / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D051381:Rats; D011921:Rats, Inbred WKY; D014184:Transplantation, Homologous; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000627:therapeutic use*
D000276:Adjuvants, Immunologic; D006912:Hydroxyquinolines; D007166:Immunosuppressive Agents; D014807:Vitamin D; C045282:roquinimex; D016572:Cyclosporine; D002117:Calcitriol; D002118:Calcium