1α,25-dihydroxycholecalciferol reduces rejection and improves survival in rat liver allografts

Vitamin D-3 affects the immuno response and improves experimental autoimmune diseases. We investigated the effect of 1,25-dihydroxycholecalciferol (1,25[OH](2)D-3) Rocaltrol as a single immunosuppresive agent and in combination with low-dose cyclosporin A (CsA) in vascularized liver allografts in rats in a high-responder strain combination (ACI double right arrow Lewis). Recipients were placed on a low-calcium diet 7 days before transplantation and were treated with 0.1 or 1 mug/kg/d 1,25(OH)(2)D-3 intraperitoneally beginning 3 days before transplantation. Treatment combining 1,25(OH)(2)D-3 with CsA (2 mg/kg/d) was also tested. Graft function and survival, histologic rejection, and concentrations of interleukin (IL)-2, -4, -10, and -12 in serum and in grafts were measured. 1,25(OH)2D3 increased allograft survival in a dose-dependent manner when compared with controls (P < .05 for both groups). Serum bilirubin, aspartate transaminase (AST), and lactate dehydrogenase (LDH) activities were significantly lower in 1,25(OH)(2)D-3-treated animals. Vitamin D reduced the concentration of IL-2 and IL-12 in serum and in grafts, and increased IL-4 and IL-10 in the grafts. The rejection activity index 10 days after transplantation was significantly lower in low- and high-dose 1,25(OH)(2)D-3-treated rats compared with vehicle-treated controls (P < .0001 for both groups). The combination of either low-dose or high-dose vitamin D3 and CsA prolonged graft survival when compared with low-dose CsA only (P < .05 for both groups). After 3 weeks, hypercalcemia developed in high-dose 1,25(OH)(2)D-3-treated rats. It is concluded that 1,23(OH)(2)D-3 prolongs survival of liver allografts in rats by decreasing the severity of acute rejection. Analogues of vitamin D with fewer hypercalcemic effects may have potential as immunosuppressive drugs in liver transplantation.