Redaelli Claudio A, Wagner Markus, Günter-Duwe Daniela, Tian Ying-Hua, Stahel Philip F, Mazzucchelli Luca, Schmid Ralph A, Schilling Martin K
Department of Visceral and Transplantation Surgery, University of Bern, Bern, Switzerland.
Kidney Int. 2002 Jan;61(1):288-96. doi: 10.1046/j.1523-1755.2002.00101.x.
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.
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.
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.
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.
长期以来人们发现维生素D3及其代谢产物在体内和体外均具有免疫抑制作用。本研究调查了1α,25-二羟胆钙化醇（1,25DHC）对大鼠血管化肾移植的影响。
在移植前三天，两组动物接受1,25DHC（1微克/千克/天，腹腔注射）和低钙饮食，持续至实验结束。切除受体器官，将单个同种异体移植物移植到高反应性品系组合（ACI→Lewis）中。移植后，两个实验组的受体开始给予低剂量环孢素A（3.2毫克/千克/天，CsA）（一组额外接受1,25DHC），而对照同种异体移植受体不接受免疫抑制（对照III）。监测移植物存活和肾功能直至死亡或实验结束，并使用Banff分类法对同种异体移植排斥反应进行组织学评估。
与对照III相比，1,25DHC显著延长了同种异体移植物的存活时间（9.6±1天对5.7±0.2天；P=0.009）。此外，与单独给予CsA相比，1,25DHC与低剂量CsA联合使用可提高同种异体移植物的存活时间（24±0.9天对13±0.3天；P=0.008）。与对照III相比，1,25DHC可维持肾肌酐清除率并降低蛋白尿，1,25DHC与低剂量CsA联合使用在保护肾功能方面再次显示出相加作用。1,25DHC和低剂量CsA均降低了血清和同种异体移植物中白细胞介素（IL）-2和IL-12的表达水平，联合治疗对IL-2和IL-12表达的减弱作用最强。此外，1,25DHC可提高同种异体移植物中IL-4和IL-10的表达水平，而单独使用CsA不会改变IL-4和IL-10的表达。相反，1,25DHC与低剂量CsA联合使用可显著提高IL-10的表达水平，而IL-4的表达未升高。
1,25DHC单一疗法可显著延长大鼠同种异体肾移植物的存活时间并保留移植物功能。与单独给予1,25DHC相比，1,25DHC与CsA联合使用对移植物存活具有相加作用，并对促炎和抗炎细胞因子有不同的调节作用。
