The First Department of Gastrointestinal Surgery, Affiliated Hospital of Putian University, Putian, Fujian 351100, P.R. China.
Department of Colorectal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China.
Mol Med Rep. 2021 Feb;23(2). doi: 10.3892/mmr.2020.11783. Epub 2020 Dec 15.
Atezolizumab can reduce immunosuppression caused by T lymphocyte apoptosis in various cancer types. The current study aimed to investigate whether this drug can also alleviate immunosuppression during sepsis. For that purpose, a C57BL/6 mouse sepsis model was generated. Mice were randomly assigned to three groups: Sham, cecal ligation and puncture (CLP) and atezolizumab groups. Atezolizumab was administered in vivo by intraperitoneal injection. The expression of programmed death ligand‑1 (PD‑L1) on neutrophils and programmed death‑1 (PD‑1) on T lymphocytes was evaluated, and endotoxin concentration, intestinal permeability, ileum histopathological score and tight junction protein expression were assessed to determine the extent of disease in each group. The rate of T lymphocyte apoptosis was determined to assess the effects of atezolizumab on T lymphocyte apoptosis in vivo and in vitro. Survival times were also recorded to compare mouse prognosis during sepsis. In the CLP group, the proportion of PD‑L1+ neutrophils was significantly higher at 48, 72 and 96 h in blood, and at 24, 48, 72 and 96 h in bone marrow, compared with those of the sham group (P<0.05). The proportion of PD‑1+ T lymphocytes was also upregulated at 72 h in blood. In the atezolizumab group, endotoxin concentration, intestinal permeability and ileum histopathological score were lower compared with those in the CLP group (P<0.05), whereas the expression of claudin‑1 and occludin proteins on ileum was higher compared with that in the CLP group (P<0.05). Both in vivo and in vitro experiments indicated that the rate of T lymphocyte apoptosis following atezolizumab treatment was lower compared with that in the CLP group (P<0.05). Survival analysis demonstrated that mice in the atezolizumab group survived longer compared with those in the CLP group (P<0.05). The current study demonstrated that treatment with atezolizumab may be an effective method for treating immunosuppression induced by sepsis.
阿特珠单抗可减少各种癌症类型中 T 淋巴细胞凋亡引起的免疫抑制。本研究旨在探讨该药是否也能减轻脓毒症期间的免疫抑制。为此，建立了 C57BL/6 小鼠脓毒症模型。将小鼠随机分为三组：假手术组、盲肠结扎穿孔（CLP）组和阿特珠单抗组。阿特珠单抗通过腹腔注射进行体内给药。评估中性粒细胞程序性死亡配体-1（PD-L1）和 T 淋巴细胞程序性死亡-1（PD-1）的表达，评估内毒素浓度、肠道通透性、回肠组织病理学评分和紧密连接蛋白表达，以确定每组疾病的严重程度。还测定了 T 淋巴细胞凋亡率，以评估阿特珠单抗对 T 淋巴细胞凋亡的体内和体外作用。记录存活时间以比较脓毒症期间小鼠的预后。在 CLP 组中，与 sham 组相比，血液中 PD-L1+中性粒细胞的比例在 48、72 和 96 小时，骨髓中 PD-L1+中性粒细胞的比例在 24、48、72 和 96 小时显著升高（P<0.05）。血液中 PD-1+T 淋巴细胞的比例在 72 小时也上调。在阿特珠单抗组中，与 CLP 组相比，内毒素浓度、肠道通透性和回肠组织病理学评分较低（P<0.05），而回肠中 Claudin-1 和 Occludin 蛋白的表达较高（P<0.05）。体内和体外实验均表明，阿特珠单抗治疗后 T 淋巴细胞凋亡率低于 CLP 组（P<0.05）。生存分析表明，阿特珠单抗组的小鼠比 CLP 组存活时间更长（P<0.05）。本研究表明，阿特珠单抗治疗可能是治疗脓毒症引起的免疫抑制的有效方法。
