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Alleviation of exhaustion-induced immunosuppression and sepsis by immune checkpoint blockers sequentially administered with antibiotics—analysis of a new mathematical model
Intensive Care Medicine Experimental Pub Date : 2019-06-11 , DOI: 10.1186/s40635-019-0260-3
Avi Gillis 1 , Michael Beil 2 , Karin Halevi-Tobias 1 , Peter Vernon van Heerden 3 , Sigal Sviri 2 , Zvia Agur 1
Affiliation  

BackgroundSepsis-associated immune dysregulation, involving hyper-inflammation and immunosuppression, is common in intensive care patients, often leading to multiple organ dysfunction and death. The aim of this study was to identify the main driving force underlying immunosuppression in sepsis, and to suggest new therapeutic avenues for controlling this immune impairment and alleviating excessive pathogen load.MethodsWe developed two minimalistic (skeletal) mathematical models of pathogen-associated inflammation, which focus on the dynamics of myeloid, lymphocyte, and pathogen numbers in blood. Both models rely on the assumption that the presence of the pathogen causes a bias in hematopoietic stem cell differentiation toward the myeloid developmental line. Also in one of the models, we assumed that continuous exposure to pathogens induces lymphocyte exhaustion. In addition, we also created therapy models, both by antibiotics and by immunotherapy with PD-1/PD-L1 checkpoint inhibitors. Assuming realistic parameter ranges, we simulated the pathogen-associated inflammation models in silico with or without various antibiotic and immunotherapy schedules.ResultsComputer simulations of the two models show that the assumption of lymphocyte exhaustion is a prerequisite for attaining sepsis-associated immunosuppression, and that the ability of the innate and adaptive immune systems to control infections depends on the pathogen’s replication rate. Simulation results further show that combining antibiotics with immune checkpoint blockers can suffice for defeating even an aggressive pathogen within a relatively short period. This is so as long as the drugs are administered soon after diagnosis. In contrast, when applied as monotherapies, antibiotics or immune checkpoint blockers fall short of eliminating aggressive pathogens in reasonable time.ConclusionsOur results suggest that lymphocyte exhaustion crucially drives immunosuppression in sepsis, and that one can efficiently resolve both immunosuppression and pathogenesis by timely coupling of antibiotics with an immune checkpoint blocker, but not by either one of these two treatment modalities alone. Following experimental validation, our model can be adapted to explore the potential of other therapeutic options in this field.

中文翻译:

免疫检查点阻滞剂与抗生素序贯给药缓解疲劳诱导的免疫抑制和败血症——新数学模型分析

背景脓毒症相关的免疫失调,包括过度炎症和免疫抑制,在重症监护患者中很常见,通常会导致多器官功能障碍和死亡。本研究的目的是确定脓毒症免疫抑制的主要驱动力,并提出控制这种免疫损伤和减轻过度病原体负荷的新治疗途径。方法我们开发了病原体相关炎症的两种简约(骨骼)数学模型,专注于血液中髓细胞、淋巴细胞和病原体数量的动态变化。两种模型都依赖于病原体的存在导致造血干细胞向髓系发育线分化的假设。同样在其中一个模型中,我们假设持续接触病原体会导致淋巴细胞衰竭。此外,我们还通过抗生素和 PD-1/PD-L1 检查点抑制剂的免疫疗法创建了治疗模型。假设实际参数范围,我们在计算机中模拟了病原体相关炎症模型,有或没有各种抗生素和免疫治疗方案。结果这两个模型的计算机模拟表明,淋巴细胞耗竭的假设是实现脓毒症相关免疫抑制的先决条件,并且先天性和适应性免疫系统控制感染的能力取决于病原体的复制率。模拟结果进一步表明,将抗生素与免疫检查点阻滞剂相结合,即使是在相对较短的时间内,也足以击败侵略性病原体。只要在诊断后立即服用药物,情况就会如此。相比之下,当作为单一疗法应用时,抗生素或免疫检查点阻滞剂无法在合理的时间内消除侵袭性病原体。结论我们的结果表明,淋巴细胞耗竭在脓毒症中至关重要地驱动免疫抑制,并且可以通过及时联合抗生素有效解决免疫抑制和发病机制使用免疫检查点阻滞剂,但不能单独使用这两种治疗方式中的任何一种。经过实验验证,我们的模型可以适应探索该领域其他治疗选择的潜力。抗生素或免疫检查点阻滞剂无法在合理的时间内消除侵袭性病原体。结论我们的结果表明,淋巴细胞耗竭在脓毒症中至关重要地驱动免疫抑制,并且可以通过及时将抗生素与免疫检查点阻滞剂结合来有效地解决免疫抑制和发病机制,但不能仅通过这两种治疗方式中的任何一种。经过实验验证,我们的模型可以适应探索该领域其他治疗选择的潜力。抗生素或免疫检查点阻滞剂无法在合理的时间内消除侵袭性病原体。仅通过这两种治疗方式中的任何一种。经过实验验证,我们的模型可以适应探索该领域其他治疗选择的潜力。但不能仅通过这两种治疗方式中的任何一种。经过实验验证,我们的模型可以适应探索该领域其他治疗选择的潜力。但不能仅通过这两种治疗方式中的任何一种。经过实验验证,我们的模型可以适应探索该领域其他治疗选择的潜力。
更新日期:2019-06-11
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