Therapeutic Effect of an Anti-Human Programmed Death-Ligand 1 (PD-L1) Nanobody on Polymicrobial Sepsis in Humanized Mice.
Therapeutic Effect of an Anti-Human Programmed Death-Ligand 1 (PD-L1) Nanobody on Polymicrobial Sepsis in Humanized Mice.
复制标题
抗人程序性死亡配体 1 (PD-L1) 纳米抗体对人源化小鼠多种微生物脓毒症的治疗作用。
DOI：
10.12659/msm.926820
复制
发表时间：
2021-01-09
期刊：
影响因子：
--
通讯作者：
Deng XM
中科院分区：
文献类型：
--
作者：
Zhao ZZ;Wang XL;Xie J;Chen LP;Li Q;Wang XX;Wang JF;Deng XM
免疫抑制被认为是脓毒症死亡的主要原因。抗程序性死亡配体1(PD-L1)治疗有望逆转脓毒症诱导的免疫抑制，但尚无证据表明可用于此适应症的商用抗PD-L1药物。本研究旨在探讨抗PD-L1纳米抗体(KN035)对脓毒症的治疗作用。用流式细胞仪检测PD-L1人源化小鼠体内PD-L1的表达水平。采用酶联免疫吸附试验检测不同剂量、不同时间点的KN035血药浓度。PD-L1人源化小鼠分为4组：假手术组、盲肠结扎穿孔(CLP)组、同型(同型+CLP)组和PD-L1(KN035+CLP)组。观察7天存活率以考察CLP小鼠的预后。用小鼠肺和肝脏的组织病理学评分评估疾病的严重程度。根据脾细胞凋亡和细菌清除情况评估免疫状态。CLP术后外周血淋巴细胞、单核细胞和中性粒细胞中PD-L1水平显著升高。KN035血药浓度显示2.5 mg/kg有可能成为KN035治疗的理想剂量。生存分析显示，KN035与术后第7天的死亡率显著降低有关(P=0.0083)。组织病理学检查显示，KN035可减轻脓毒症所致的肺、肝损伤。KN035可减少CLP小鼠脾组织中的凋亡细胞数，并几乎消除了腹腔灌洗液中的细菌菌落。KN035是一种抗PD-L1抗体，可提高CLP小鼠的存活率，减轻脓毒症诱导的脾细胞凋亡。
Immunosuppression is regarded as the main cause of death induced by sepsis. Anti-programmed death-ligand 1 (PD-L1) therapy is promising in reversing sepsis-induced immunosuppression but no evidence is available on use of commercially available anti-PD-L1 medications for this indication. The present preclinical study was performed to investigate the therapeutic effect of an anti-PD-L1 nanobody (KN035) in sepsis. The level of expression of PD-L1 in PD-L1 humanized mice was confirmed with flow cytometry. Plasma concentrations of KN035 at different dosages at different time points were detected using an enzyme-linked immunosorbent assay. PD-L1 humanized mice were allocated into 4 groups: sham, cecal ligation and puncture (CLP), isotype (isotype+CLP), and PD-L1 (KN035+CLP). The 7-day survival rate was observed to investigate outcomes in CLP mice. Disease severity was assessed with histopathological scoring of mice lungs and livers. Immune status was assessed based on cell apoptosis in the spleen and bacterial clearance. PD-L1 levels were significantly elevated in peripheral lymphocytes, monocytes, and neutrophils after CLP surgery. Blood concentrations of KN035 showed that 2.5 mg/kg had potential to be an ideal dosage for KN035 therapy. Survival analysis demonstrated that KN035 was associated with significantly reduced mortality on Day 7 after surgery (P=0.0083). The histopathological tests showed that KN035 alleviated sepsis-induced injury in the lungs and liver. KN035 reduced the number of apoptotic cells in the spleen and almost eliminated bacterial colonies in the peritoneal lavage fluid from the CLP mice. KN035, an anti-PD-L1 antibody, can improve the rate of survival in CLP mice and alleviate sepsis-induced apoptosis in the spleen.