阻断共刺激信号在异种小动物心脏移植中诱导免疫耐受的研究

Study of Immune Tolerance to Cardiac Xenografts Induced by Blockading B7/CD28 and CD40/CD40L Interactions in Guinea-pig to Rat

目的在非协调性异种小动物豚鼠-大鼠心脏移植模型当中,通过单克隆抗体阻断T细胞B7/CD28及CD40/CD40L激活通路途径来探讨T细胞在异种移植延迟性免疫排斥中的作用,探索诱导异种移植T细胞外周耐受的可能性。方法将供体三色豚鼠和受体SD大鼠随即分成四组:A组(对照组),在移植前一天大鼠腹腔内注射CVF 0.4mg/kg;B组(B7mAb组),在移植当天大鼠腹腔内注射B7单抗0.1mg,余处理同A组;C组(CD40LmAb组),在移植当天大鼠腹腔内注射CD154单抗0.1mg,余处理同A组;D组(联合组),在移植当天大鼠腹腔内注射B7单抗0.1mg、CD154单抗0.1mg,余处理同A组。观察各组供心存活的时间,并行移植心脏的常规病理和免疫组化检查。结果对照组移植心脏的存活时间为(19.5±2.7)h,与对照组比较,B7组、CD40L组和联合处理组的移植心脏存活时间均得到了显著的延长,但联合处理组延长最为明显。移植心脏组织病理学检查均呈急性血管排斥反应改变,且以CD8+T细胞浸润为主。结论联合阻断CD28/B7与CD40/CD40L共刺激通路可延长异种移植心脏存活时间。

Objective To investigate the effect of T cells on the delayed xenograft rejection by blockading B7/CD28 and CD40/CD40L interactions,and to investigate the possibility of inducing the immune tolerance to heart xenografts by the way of T cells.Methods Intra-abdominal heterotopic heart transplantation was performed.guinea-pig and SD rat were,respectively,selected as donor and recipient.Experimental animals were randomly divided into four groups：①the control group（group A）：recipients were treated with CVF by intraperitoneal injection at the dose of 0.4mg/kg on 20~24 hours before transplantation.② the B7-mAb group（group B）：recipients were treated with B7-mAb by intraperitoneal injection at the dose of 100μg before transplanting operation,the other pretreatments were the same as group A.③the CD40L-mAb group（group C）：recipients were treated with CD40L-mAb by intraperitoneal injection at the dose of 100μg before transplanting operation,the other pretreatments were the same as group A.④the union group（group D）：the recipients were treated with CVF,B7-mAb and CD40L-mAb.Observe the survival time of cardiac xenografts,when no myocardial contractions could be felt,the xenografts were excised and examined histologically and immunohistochemically for CD4＋,CD8＋ T cells.Results Mean survival time of group A（19.5±2.7）h,the graft survival time was significantly prolonged by blocking B7/CD28 and CD40/CD40L interactions.Some CD8＋ T cells（25%of total leukocytes）were found infiltrating,the entire xenografts showed acute vascular rejection.Conclusion The blockade B7/CD28 and CD40/CD40L interactions can prolong the survival of the xenografts.It may provide a new way to treat immune rejection after xenotransplantation.