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脓毒症是机体对感染的免疫反应失调而引发危及生命的多器官功能障碍[1],是感染致死的首要原因。据统计,全球每年有4 700万~5 000万脓毒症病例,脓毒症相关死亡人数至少为1 100万[2],约占全年总死亡人数的1/5。脓毒症的病理生理学过程包含宿主全身过度炎症反应和免疫抑制的复杂相互作用,其中,免疫抑制会导致院内感染和体内病毒重激活,甚至出院后长期持久的免疫失能状态,脓毒症患者在免疫麻痹期的累积病死率约为总病死率的90%[3]。脓毒症免疫麻痹主要表现为细胞因子分泌失调、抗原提呈细胞功能减弱、T细胞亚群稳态失衡[4],最终造成机会性感染的易感性增加。然而,临床上对于脓毒症的治疗手段十分有限,阻断TNF-α[5-6]、TLR4[7-8]等控制炎症级联反应的免疫抑制疗法在临床试验中也相继失败;幸运的是,纠正脓毒症免疫麻痹的免疫激活疗法异军突起,为脓毒症治疗带来了曙光,且许多疗法已被临床试验证实有效。本文对基于免疫麻痹纠正的脓毒症免疫疗法研究进展进行综述。
Research progress of immunotherapies on correction of immunoparalysis in sepsis
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摘要: 免疫麻痹是导致脓毒症中晚期患者死亡的主要原因,纠正免疫麻痹状态是脓毒症治疗的重要方向。在脓毒症的病理过程中,多种因素会导致细胞因子分泌失调,抗原提呈细胞功能减弱,淋巴细胞凋亡和耗竭,最终导致免疫麻痹、二次感染甚至患者死亡。对处于免疫麻痹状态的脓毒症患者,GM-CSF、IFN-γ、IL-7和IL-15等细胞因子,PD-1/PD-L1抗体、CTLA-4抗体、TIM-3抗体和LAG-3抗体等免疫检查点相关疗法,胸腺肽α1、免疫球蛋白等免疫活性物质都可能有利于纠正患者的免疫麻痹状态。本文对免疫治疗纠正脓毒症免疫麻痹的研究进展做一综述。Abstract: Immunoparalysis is the main cause of death in patients with intermediate and terminal sepsis. The correction of immunoparalysis is an important direction of sepsis treatment. In the pathological process of sepsis, a variety of factors contribute to the imbalanced secretion of cytokines, weakened function of antigen-presenting cells, apoptosis and depletion of lymphocytes, and ultimately lead to immunoparalysis, secondary infection, and even patient deaths. Cytokines such as GM-CSF, IFN-γ, IL-7, and IL-15, immune checkpoint-related therapies such as PD-1/PD-L1 antibodies, CTLA-4 antibodies, TIM-3 antibodies, and LAG-3 antibodies, and immunoreactive substances such as thymosin α1 and immunoglobulin might be beneficial to correct the immune paralysis of patients. the progress of immunotherapy to correct immune paralysis in sepsis were reviewed in this article.
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Key words:
- immunotherapy /
- sepsis /
- immunoparalysis /
- cytokines /
- immune checkpoint /
- immunoreactive substances
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