他克莫司处理供者树突状细胞在诱导大鼠同种心脏移植免疫耐受中的作用(英文)

Immune tolerance induced by immature dendritic cells treated with tacrolimus in rat heart transplantation

背景:诱导供者特异性免疫耐受被认为是最终克服器官移植后排斥反应的有效途径,近年来关于未成熟树突状细胞在诱导免疫耐受中的重要作用日益受到关注。目的:观察他克莫司处理的供者未成熟树突状细胞对大鼠同种异体心脏移植免疫耐受的影响,分析未成熟树突状细胞诱导免疫耐受的作用途径。设计:随机对照动物实验。材料:实验于2006-04/2006-12在青岛大学医学院附属医院动物实验中心完成。以45只Wistar大鼠为供体,45只SD大鼠为受体,行颈部心脏移植45例次。按随机数字表法分为3组,每组15例次,进行不同的预处理。方法:对照组、未经他克莫司处理组及他克莫司处理组移植前7d分别经尾静脉注射生理盐水、供者未成熟树突状细胞和他克莫司处理的未成熟树突状细胞。分别测定移植后SD大鼠与Wistar大鼠及第3品系Lewis大鼠的单向混合淋巴细胞反应。主要观察指标:各组受体大鼠移植心脏存活时间、心肌病理及血清白细胞介素2、白细胞介素4、白细胞介素10、γ-干扰素含量变化。结果:①未经他克莫司处理组大鼠的移植心脏存活时间较对照组明显延长(P<0.01),他克莫司处理组大鼠的移植心脏存活时间进一步延长(P<0.05)。②混合淋巴细胞培养结果显示为供者特异性。③各组大鼠血清白细胞介素2、γ-干扰素、白细胞介素4、白细胞介素10含量差异具有显著性意义(P<0.01)。代表Th1的白细胞介素2、γ-干扰素水平明显降低,代表Th2的白细胞介素4、白细胞介素10水平明显增高。结论:未成熟树突状细胞能够诱导同种异体大鼠心脏移植免疫耐受;他克莫司处理的未成熟树突状细胞能够加强这种免疫耐受,且这种耐受是供者特异性的。其可能主要通过调节T细胞免疫应答类型(Th1至Th2的免疫偏移)、诱导调节性T细胞和诱导T细胞失能等途径来参与免疫耐受的形成。

BACKGROUND： Immune tolerance is regarded as the most effective measure to overcome rejection. For the past few years the important effect of immature dendritic cells （imDCs） on immune tolerance has drawn close attention. OBJECTIVE： To study the effect of imDCs treated with tacrolimus （FK506） on immune tolerance in rat allograft organ transplantation and to investigate the mechanism of immune tolerance induced by imDCs. DESIGN： A randomized and controlled animal experiment. MATERIALS： The experiment was carried out at the Experimental Animal Center, the Affiliated Hospital of Medical College, Qingdao University from April 2006 to December 2006. Cervical heart transplantations were performed in which 45 Wister rats were used as donors and 45 SD rats as allograft recipients. The rats were randomly divided into three groups with 15 for each. METHODS：Normal sodium, imDCs, and imDCs treated with FK506 were injected via vena caudalis seven days before the operations respectively. Mixed lymphocyte reaction （MLR） was measured on SD, Wistar, and Lewis rats. MAIN OUTCOME MEASURES： Heart allograft survival was monitored and one-way MLR, heart pathology and the levels of interleukin-2 （IL-2）, IL-4, IL-10, and interferon- γ （IFN-γ ） in the serum were detected. RESULTS： In treatment group without FK506, heart allograft survival were prolonged after imDC injection （P 〈 0.01 ）; while their survival were prolonged further in treatment group with FK506 （P 〈 0.05）. MLR showed that the tolerance was donor specific. Analysis of variance showed that there was high significant difference for serum concentrations of IL-2, IFN- y, IL-4, and IL- 10 in the three groups （P 〈 0.01 ）. The concentrations of IL-2 and IFN-γ expressing on Thl were lower, and that of IL-4 and IL-10 expressing on Th2 were obviously higher in the latter two groups. CONCLUSION： ImDCs can induce immune tolerance in rat heterotopic heart transplantation successfully; lmDCs treated with FK506 can enhance the tolerance which is donor specific. ImDCs may induce the immune tolerance by means of modifying the immune response type of T cells （immune deflection from Thl to Th2）, mediating the generation of regulatory T cells （T-reg） and inducing T cells disenabling.