1alpha,25-dihydroxyvitamin D3 shows strong and additive immunomodulatory effects with cyclosporine A in rat renal allotransplants.
BACKGROUND
Vitamin D3 and its metabolites have long been found to exert immunosuppressive effects both in vivo and in vitro. The present study investigated the effect of 1alpha,25-dihydroxycholecalciferol (1,25DHC) on vascularized renal allografts in rats.


METHODS
Three days prior to transplantation, two groups of animals were subjected to 1,25DHC (1 microg/kg/day IP) and a low calcium diet, which was continued until the end of the experiments. Recipient organs were removed and single allografts were transplanted in a high responder strain combination (ACI --> Lewis). Following transplantation, low-dose cyclosporine A (3.2 mg/kg/day CsA) administration was started in two experimental groups of recipients (one group receiving 1,25 DHC additionally) whereas the control allograft recipients received no immunosuppression (control III). Graft survival and renal function was monitored until death or the end of experiments and allograft rejection was assessed histologically using the Banff classification.


RESULTS
1,25DHC significantly prolonged allograft survival in comparison to control III (9.6 +/- 1 vs. 5.7 +/- 0.2 days; P=0.009). In addition, a combination of 1,25DHC and low-dose CsA increased allograft survival compared to CsA administration alone (24 +/- 0.9 vs. 13 +/- 0.3 days; P=0.008). 1,25DHC preserved renal creatinine clearance and decreased proteinuria in comparison to control III, and the combination of 1,25DHC and low-dose CsA again showed an additive effect on preservation of renal function. 1,25DHC and low-dose CsA both decreased interleukin (IL)-2 and IL-12 expression levels in serum and allografts, and a combination treatment produced the strongest attenuation of IL-2 and IL-12 expression. In addition, 1,25DHC increased IL-4 and IL-10 expression levels in allografts, whereas CsA alone did not alter IL-4 and IL-10 expression. In contrast, combination of 1,25DHC and low-dose CsA showed a significant increase in IL-10 expression levels whereas IL-4 expression was not elevated.


CONCLUSIONS
Monotherapy with 1,25DHC significantly prolongs survival of renal allografts and preserves graft function in rats. A combination of 1,25DHC and CsA caused an additive effect on graft survival with differential regulation of pro- and anti-inflammatory cytokines, as compared to 1,25DHC administration alone.
Redaelli
Claudio A
CA
Department of Visceral and Transplantation Surgery, University of Bern, Bern, Switzerland. claudio.redaelli@insel.ch
Wagner
Markus
M
Günter-Duwe
Daniela
D
Tian
Ying-Hua
YH
Stahel
Philip F
PF
Mazzucchelli
Luca
L
Schmid
Ralph A
RA
Schilling
Martin K
MK
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology*; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology; D006996:Hypocalcemia / Q000139:chemically induced; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016753:Interleukin-10 / Q000032:analysis / Q000097:blood; D018664:Interleukin-12 / Q000032:analysis / Q000097:blood; D007376:Interleukin-2 / Q000032:analysis / Q000097:blood; D015847:Interleukin-4 / Q000032:analysis / Q000097:blood; D007668:Kidney / Q000737:chemistry / Q000473:pathology / Q000502:physiology; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D009336:Necrosis; D053495:Osteopontin; D051381:Rats; D011912:Rats, Inbred ACI; D011917:Rats, Inbred Lew; D012795:Sialoglycoproteins / Q000032:analysis / Q000096:biosynthesis; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000276:immunology / Q000494:pharmacology* / Q000633:toxicity
C116441:2-methyl-1,25-dihydroxyvitamin D3; D000276:Adjuvants, Immunologic; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D012795:Sialoglycoproteins; C506897:Spp1 protein, rat; D053495:Osteopontin; D016753:Interleukin-10; D014807:Vitamin D; D018664:Interleukin-12; D015847:Interleukin-4; D016572:Cyclosporine