阻断CD40-CD40L信号通路对小鼠肺移植术后闭塞性细支气管炎的影响  

Effects to obliterative bronchiolitis by blocking CD40-CD40L pathway in the mouse lung transplantation

作　　者：陈荣卷 陈其瑞[2] 许江南[1] 丁跃中[1] Chen Rongjuan;Chen Qirui;Xu Jiangnan;Ding Yuezhong(Department of Immunology,School of Basic Medical Sciences,Capital Medical University,Beijing 100069,China;Department of Thoracic Surgery,Beijing Chaoyang Hospital,Capital Medical University,Beijing 100020,China)

机构地区：[1]首都医科大学基础医学院免疫学系,北京100069 [2]首都医科大学附属北京朝阳医院胸外科,北京100020

出　　处：《首都医科大学学报》2018年第2期258-264,共7页Journal of Capital Medical University

基　　金：国家自然科学基金(81370188)~~

摘　　要：目的本研究使用抗CD40L抗体(克隆号:MR1)阻断CD40-CD40L信号通路,利用小鼠原位左肺移植模型,对比其与传统免疫抑制剂环孢素/甲泼尼龙对小鼠术后移植物闭塞性细支气管炎(obliterative bronchiolitis,OB)的治疗效果,并进一步评估其对移植物术后损伤的影响及相应机制,为临床肺移植术后治疗方法提供新思路。方法构建小鼠原位左肺移植模型,以野生型Balb/c小鼠作为供体小鼠,野生型C57BL/6小鼠作为受体小鼠。移植术后10 d,牺牲小鼠,采用苏木精/伊红(hematoxylineosin,HE)染色、Masson染色以及中性粒细胞特异性染色(抗髓过氧化物酶),观察各组移植左肺的组织病理学改变,利用实时荧光定量聚合酶链式反应(polymerase chain reaction,PCR)技术检测移植物中白细胞介素-17A(interleukin-17A,IL-17A)mRNA的表达水平的变化。结果术后10 d,注射了环孢素/甲泼尼龙和抗CD40L抗体治疗的小鼠,移植左肺外观体积增大;病理结果显示抗CD40L抗体治疗组较环孢素/甲泼尼龙治疗组炎性细胞浸润和OB现象得到有效缓解(P<0.05),中性粒细胞浸润显著减少(P<0.01);抗CD40L抗体治疗组移植物中IL-17A mRNA表达水平,较环孢素/甲泼尼龙治疗组显著降低(P<0.01)。结论利用抗CD40L抗体阻断CD40-CD40L信号通路能够有效保护移植物细支气管上皮,缓解小鼠肺移植术后急性排斥和OB反应以及小气道损伤,且效果优于传统抑制剂环孢素/甲泼尼龙。Objective Our research focus on the effects to obliterative bronchiolitis(OB)by blocking CD40-CD40L pathway with anti-mCD40L on allografts in mouse orthotopic lung transplantation model,and comparing with traditional immunosuppressive agents-cyclosporine/methylprednisolone(C/M)to explore new clinical treatment methods.Methods Murine orthotopic lung transplantation was performed in wild type C57BL/6 mice using Balb/c donors.At day 10,histopathologic characteristics were assessed by hematoxylin-eosin(HE)staining,Masson staining and neutrophil staining with antimyeloperoxidase;real-time polymerase chain reaction(RT-PCR)was performed for interleukin-17A(IL-17A)expressions.Results Donor lung of recipients were harvested at 10 days after transplantation.Groups with treatment of anti-mCD40L and cyclosporine/methylprednisolone showed an enlargement appearance compared with allograft group.Pathology results demonstrated that administration of anti-mCD40L can better improve rejection injury and OB compared with cyclosporine/methylprednisolone treatment group(P<0.05).Furthermore,administration of anti-mCD40L significantly reduced transcription levels of IL-17A in grafts(P<0.01).Conclusion This findings demonstrated that by blocking CD40-CD40L pathway with anti-mCD40L can better alleviate transplant rejection and OB mediated by IL-17A in mouse lung transplantation.

关 键 词：小鼠原位左肺移植 抗CD40L抗体(MR1) 环孢素/甲泼尼龙 闭塞性细支气管炎 

分 类 号：R392.4[医药卫生—免疫学]