1 alpha,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 immunosuppressive agent and in combination with low-dose cyclosporin A (CsA) in vascularized liver allografts in rats in a high-responder strain combination (ACI-->Lewis). Recipients were placed on a low-calcium diet 7 days before transplantation and were treated with 0.1 or 1 microg/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)(2)D(3) 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 D(3) 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 1,25(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.
Redaelli
C A
CA
Department of Visceral and Transplantation Surgery, University of Bern, Bern, Switzerland.
Wagner
M
M
Tien
Y H
YH
Mazzucchelli
L
L
Stahel
P F
PF
Schilling
M K
MK
Dufour
J F
JF
D000818:Animals; D002117:Calcitriol / Q000009:adverse effects / Q000627:therapeutic use*; D002120:Calcium Channel Agonists / Q000009:adverse effects / Q000627:therapeutic use*; D016572:Cyclosporine / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D006084:Graft Rejection / Q000473:pathology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects*; D006934:Hypercalcemia / Q000139:chemically induced; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D016753:Interleukin-10 / Q000097:blood / Q000378:metabolism; D007376:Interleukin-2 / Q000097:blood / Q000378:metabolism; D015847:Interleukin-4 / Q000097:blood / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D016031:Liver Transplantation; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D014184:Transplantation, Homologous
D002120:Calcium Channel Agonists; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D016753:Interleukin-10; D015847:Interleukin-4; D016572:Cyclosporine; D002117:Calcitriol