Two novel vitamin D analogues, KH 1060 and CB 966, prolong skin allograft survival in mice.
KH 1060 and CB 966, two novel analogues of 1,25-dihydroxyvitamin D3(1,25(OH)2D3), were found to significantly delay the rejection of allogeneic skin grafts in CBA (H-2k) recipient mice, transplanted with skin from C57Bl/6 (H-2b) donor mice. Graft survival was assessed in mice treated with KH 1060 or CB 966 until the day of rejection, in comparison to mice treated with vehicle, 1,25(OH)2D3 or cyclosporin A (CsA). The mean graft survival time in days was found to be: 16.6 +/- 0.5 (CsA, 20 mg/kg/day orally (p.o.); 13.9 +/- 0.6 and 15.5 +/- 0.6 (1,25(OH)2D3, 0.2 and 0.4 microgram/kg/day intraperitoneally (i.p.)); 14.3 +/- 0.2 and 18.7 +/- 0.5 (CB 966, 0.2 and 0.4 microgram/kg/day i.p.); 13.7 +/- 0.8, 15.7 +/- 1.7, 18.2 +/- 2.7 and 24.5 +/- 0.5 (KH 1060, 0.02, 0.1, 0.2 and 0.4 microgram/kg/day i.p.). Mean graft survival in days for control mice was: 10.3 +/- 0.2 (vehicle for injection, i.p.) and 11.5 +/- 0.2 (olive oil, p.o.). Serum calcium levels, measured on the day of rejection, rose moderately after treatment with either KH 1060 or CB 966. Combination of CsA (20 mg/kg/day p.o.) with KH 1060 (0.1 microgram/kg/day i.p.) resulted in an additive or synergistic effect: 23.4 +/- 1.1 days of skin allograft survival, compared to 15.7 +/- 1.7 days with KH 1060 alone, and 15.1 +/- 1.9 days with CsA alone. KH 1060 was the most active of the tested compounds and can therefore be regarded as a potent immunosuppressor in transplantation; it can be used in combination with CsA and is effective at doses which only marginally affect serum calcium levels.
Veyron
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P
Hôpital Edouard-Herriot, Lyon, France.
Pamphile
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R
Binderup
L
L
Touraine
J L
JL
D000818:Animals; D002117:Calcitriol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D016572:Cyclosporine / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006085:Graft Survival / Q000187:drug effects*; D006183:H-2 Antigens; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D016038:Skin Transplantation / Q000276:immunology*; D014184:Transplantation, Homologous
D006183:H-2 Antigens; D007166:Immunosuppressive Agents; C074279:KH 1060; D016572:Cyclosporine; D002117:Calcitriol