造血干细胞移植后出血性膀胱炎免疫损伤机制及其干预研究

异基因造血干细胞移植术后出血性膀胱炎（HC）是移植常见合并症，严重影响生活质量乃至危及生命。HC发病机制不清，缺乏针对性治疗手段。病毒感染是HC主要危险因素但不能解释发病，课题组前期发现糖皮质激素治疗HC作用，形成“二次打击”免疫损伤假说；发现病毒继发HC患者髓源抑制细胞/激活性单核细胞失衡，与尿液单核-巨噬细胞因子 IL-6、IL-8、TNF-a高表达、炎性小体-焦亡信号NLRP3/IL-1β高表达密切相关，提示“病毒感染—免疫损伤”在HC发病潜在作用。本项目拟以HC发病的“二次打击”免疫损伤为核心，以HC尿液炎症因子为切入点，结合课题组建立的HCMV感染人源化小鼠模型及前瞻临床队列，聚焦HC炎症因子与天然免疫细胞相互作用，探讨细胞学机制，从“病毒侵袭”以外的全新角度阐明HC发病机制，为基于免疫损伤危险分层的HC干预方法奠定基础。

Hemorrhagic cystitis (HC) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT).The pathogenesis of HC is not clear, therefore the effective interventions have been limited. Virus infection is top risk factor for HC, however, pathogenesis of HC is not only related to infection. Our team establish the “Double-Hit” hypothesis of HC based on the successful application of glucocorticoid; then the imbalance between myeloid suppressor cells(MDSCs) and activated monocytes, activated monokines (IL-6、IL-8、TNF-a) in urine, and NLRP3 / IL-1 β associated pyroptosis had been identified to support the potential role of “Virus infection—Immune Injury” in pathogenesis of HC. Based on CMV infected humanized mice model established by our team and prospective registered study, this project will focus on the interaction of the above cytokines with the natural immune cells, explore the cellular mechanism and potential targeting methods, try to establish stratified interventions based on immune Injury for HC.