IL-17介导的肺移植后闭塞性细支气管炎的细胞与分子调控机制及干预研究

Obliterative bronchiolitis (OB) remains the biggest obstacle for long-term graft survival after lung transplantation, severely hindering its clinical applications and resulting in significant economic burden and life loss. Determining the cellular and molecular mechanisms of OB pathogenesis and discovering effective reagents and methods for its regulation and intervention after lung transplantation has been being one of the most difficult and challenging tasks in transplant immunity research. Basing on our previous studies, the novel orthotropic mouse lung transplantation model in which Stat6/T-bet double deficient mice were used as recipients showed an IL-17 dominant transplant rejection with characteristics of OB pathogenesis. In this proposal, we will utilize this novel lung transplantation model to elucidate the cellular and molecular mechanisms of IL-17 mediated lung transplant rejection and OB pathogenesis. We will also explore the possibility to use IFNβ for IL-17 suppression and OB prevention, Reparixin (an inhibitor of CXCR1/2) for limiting neutrophil migration and activation, and in combination with anti-CD154 mAbs for blocking CD40-CD154 costimulation to achieve long-term lung transplant survival and tolerance. Together, results obtained from our research will uncover novel mechanisms, molecules and signal pathways that contribute to OB pathogenesis after lung transplantation, and provide new targets, pathways and strategies for effective clinical treatments of lung transplant rejection.

肺移植后闭塞性细支气管炎（OB）是导致移植肺长期存活率低的最重要因素，严重限制和阻碍了肺移植的临床应用，并造成生命资源的极大损失。探索和确定OB的发病机制并寻求有效干预手段，是移植免疫学和肺移植研究的难点和热点。细胞因子IL-17对OB的形成和移植肺的长期存活影响显著，我们前期研究发现Stat6/T-bet双基因敲除小鼠为受体的原位肺移植模型能全面真实地反映肺移植排斥反应和OB的病理过程。在此基础上，本项目提出利用上述新型动物模型研究IL-17介导的肺移植后OB发病机制，并确定IL-17对中性粒细胞的募集活化在肺移植排斥反应和OB中的作用；首次提出利用IFNβ、CXCR1/2阻断剂抑制肺移植后IL-17表达、中性粒细胞募集活化和OB形成，并探索抗CD154单抗与IFNβ或CXCR1/2阻断剂联合应用诱导移植免疫耐受并改善移植肺长期存活率的干预新手段，为防治肺移植排斥反应提供可借鉴的新策略。

肺移植后闭塞性细支气管炎（OB）是导致移植肺长期存活率低的最重要因素，严重限制和阻碍了肺移植的临床应用。细胞因子IL-17对OB的形成和移植肺的长期存活影响显著，但IL-17介导肺移植排斥反应和OB病理进程的细胞与分子调控机制不明确。项目在前期研究基础上，提出利用Stat6/T-bet双基因敲除（DKO）小鼠为受体的原位肺移植模型，研究IL-17介导的肺移植后OB发病机制，并探索改善移植肺长期存活率的干预新手段。.项目在以DKO小鼠为受体的新型肺移植模型基础上，加入手术操作更为简易的小鼠原位气管移植模型作为补充，模拟肺移植术后早期的排斥反应，证实了IL-17和Th17分化信号是参与并促进肺/气管移植后排斥反应和气道上皮损伤的主导因素。我们发现移植肺浸润T细胞中CD8+ T细胞所占比例与移植肺的排斥病理损伤程度正相关，明确了CD8+ T细胞是直接参与肺/气管移植排斥反应和气道上皮损伤的关键细胞，并可能在移植后早期加速IL-17产生和OB进展，最终影响移植肺/气管的功能和长期存活；我们还证实了中性粒细胞通过募集活化的方式参与IL-17介导的移植气道炎症反应和上皮细胞损伤，并形成 “IL-17/中性粒细胞/CD8+ T细胞反应轴”。针对以上调控作用机制，我们分析评估了多种干预手段对移植后气道上皮损伤和OB病理进程的影响，为提高肺移植的长期存活率、改善患者的长期预后提供了可借鉴的免疫治疗新策略。