Blockade Of PD-1 Attenuated Postsepsis Aspergillosis Via The Activation of IFN-γ and The Dampening of IL-10
Blockade Of PD-1 Attenuated Postsepsis Aspergillosis Via The Activation of IFN-γ and The Dampening of IL-10
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DOI：
10.1097/shk.0000000000001392
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发表时间：
2020-04-01
期刊：
影响因子：
3.1
通讯作者：
Leelahavanichkul, Asada
中科院分区：
文献类型：
--
作者：
Chau Tran Bao Vu;Thammahong, Arsa;Leelahavanichkul, Asada
背景：在过去的几年中，脓毒症患者中出现了医院内曲霉菌感染。阻断PD-1/PD-L通路可改善细菌性脓毒症和脓毒症后继发真菌感染的转归，已成为一种有前途的治疗策略。近年来，PD-1受体阻滞剂对曲霉病等感染性疾病的作用已有争议，因此，抗PD-1药物的疗效仍有待阐明。方法：采用盲肠结扎穿刺术(CLP)建立小鼠脓毒症模型，于CLP后第5天免疫细胞耗尽时静脉接种烟曲霉孢子。曲霉感染后，两性霉素B联合或不联合抗PD-1治疗。结果：单用两性霉素B不能有效治疗CLP小鼠继发性曲霉病。相反，抗真菌药物配合抗PD-1治疗减轻了血液和内脏的真菌负担，并提高了继发性曲霉病小鼠的存活率。PD-1阻断的这些结果伴随着脾细胞CD86表达的增强，血清干扰素-γ的增加，以及IL-10的抑制。来自抗PD-1处理的小鼠的激活的T细胞也极大地增加了干扰素-γ，减少了IL-10的产生。结论：PD-1对脓毒症后曲霉病的抑制作用可能是通过上调CD86表达和干扰素-γ的产生，使衰竭的抗原提呈细胞和T细胞恢复活力，抑制IL-10的产生，从而减轻继发性曲霉病的发生。抗PD-1辅助治疗有望成为抗致死性真菌感染高级免疫治疗的一种有前景的策略。
Background: Nosocomial aspergillosis in patients with sepsis has emerged in the past few years. Blockade of PD-1/PD-L pathway has tended to become a promising therapeutic strategy as it improved the outcome of bacterial sepsis and postsepsis secondary fungal infection. Recently, the controversial effects of PD-1 blockade on infectious diseases, including aspergillosis, have been demonstrated; therefore, the efficacy of anti-PD-1 drug still remains to be elucidated. Methods: Cecal ligation and puncture (CLP) was conducted as a mouse sepsis model.Aspergillus fumigatusspores were intravenously inoculated on day 5 post-CLP, when the immune cells succumbed to exhaustion. Amphotericin B was medicated together with or without anti-PD-1 treatment afterAspergillusinfection. Results: Amphotericin B alone was not effective to treat the CLP-mice with secondary aspergillosis. In contrast, antifungal medication with the adjunctive anti-PD-1 treatment attenuated the fungal burdens in blood and internal organs, and improved the survival rate of the mice with secondary aspergillosis. These outcomes of PD-1 blockade were concurring with the enhanced CD86 expression on splenocytes, the augmented serum IFN-gamma, and the dampened IL-10. Activated T cells from anti-PD-1-treated mice also highly increased IFN-gamma and diminished IL-10 production. Conclusion: The blockade of PD-1 on postsepsis aspergillosis presumably reinvigorated exhausted antigen-presenting cells and T cells by upregulating CD86 expression and IFN-gamma production, and dampened IL-10 production, which consequently leaded to the attenuation of secondary aspergillosis. The adjunctive anti-PD-1 therapy may become a promising strategy for the advanced immunotherapy against lethal fungal infection.