脓毒症和PICS综合征人源化动物模型构建及PD-1/PD-L1信号在免疫抑制启动和免疫衰竭建立的作用机制研究

Because of comorbidities and immune senescence, the immune system of elderly patients with sepsis showed immunoparalysis following once or several times after the onset of sepsis, and developed persistent inflammatory, immunosuppressed, catabolic syndrome (PICS). In other words, the immunesuppression is initiated by sepsis, and its persistence induced PICS characterized by immunoparalysis. The disorder of PD-1/PD-L1 signalling is the key mechanism for initiation of immunosuppression in sepsis and establishment of immunoparalysis in PICS, and a prospective therapeutic target for immunotherapy of sepsis. However, these viewpoints are derived from the investigation of traditional animal model of sepsis and the analysis of static clinical sample, which limits their reliability and clinical application. At present, it is urgent to develop a novel animal model which can objectively reflect the septic immune response and carry out dynamic analysis of immune reaction. Accordingly, we prepare to construct humanized animal model of sepsis and PICS, and discuss the mechanism of PD-1/PD-L1 signaling in initiation of immunesuppression and establishment of immunoparalysis. It will deepen the understanding of initiation of immunosuppression in sepsis and establishment of immunoparalysis in PICS, and provide a new way for their immunotherapy.

基础疾病和免疫衰老导致老年脓毒症患者的免疫系统在经受一次或多次脓毒症打击后进入免疫衰竭状态，并发展为PICS综合征；换而言之，脓毒症诱发免疫抑制，持续性免疫抑制导致脓毒症发展为PICS综合征，其临床特征是免疫衰竭；PD-1/PD-L1信号失调是脓毒症诱发免疫抑制和PICS综合征免疫衰竭建立的核心机制，并且是脓毒症免疫治疗的前瞻性治疗靶点。但这些认识源于“传统的”脓毒症动物模型研究和“静态的”临床样本分析，这限制了这些研究结论的可靠性和临床应用。目前，迫切需要模拟脓毒症患者免疫应答的动物模型来开展动态的免疫反应分析。据此，本研究团队拟构建脓毒症和PICS综合征人源化动物模型并探讨PD-1/PD-L1信号在免疫抑制启动和免疫衰竭建立的作用机制；这将加深对脓毒症诱发免疫抑制和PICS综合症免疫衰竭建立的认识，为脓毒症和PICS综合征的免疫治疗提供新思路。

基础疾病和免疫衰老导致老年脓毒症患者的免疫系统在经受一次或多次脓毒症打击后进入免疫衰竭状态，并发展为PICS综合征；换而言之，脓毒症诱发免疫抑制，持续性免疫抑制导致脓毒症发展为PICS综合征，其临床特征是免疫衰竭；PD-1/PD-L1信号失调是脓毒症诱发免疫抑制和PICS综合征免疫衰竭建立的核心机制，并且是脓毒症免疫治疗的前瞻性治疗靶点。但这些认识源于“传统的”脓毒症动物模型研究和“静态的”临床样本分析，这限制了这些研究结论的可靠性和临床应用。本项目通过构建脓毒症和PICS综合征人源化动物模型，分析PD-1/PD-L1信号在免疫抑制发展为免疫衰竭过程中的变化，分析抑制PD-1/PD-L1信号在预防和逆转免疫麻痹的作用；本项目成功构建了脓毒症和PICS综合征人源化动物模型；通过对上述动物模型的综合分析表明：经历第二次脓毒打击后，PICS综合征人源化动物模型的HLA-DR+CD14+细胞比例低于30%，PD-L1的表达高于5%，HLA-DR+CD14+PD-L1+是PICS状态的特异性天然免疫细胞指标；经历第二次脓毒打击后，PICS综合征人源化动物模型的Treg细胞比例高于5%，PD-1的表达高于4%，Treg-PD-1是PICS状态的特异性诱导免疫细胞指标；经建模分析表明，HLA-DR+CD14+PD-L1+和Treg-PD-1是判别PICS的最优指标，其临界值分别是3.6%和1.8%；PD-1单抗治疗可预防和逆转免疫麻痹和改善免疫状态。