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.