Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
J Leukoc Biol. 2018 Jan;103(1):23-33. doi: 10.1002/JLB.5HI0917-360R. Epub 2017 Dec 21.
Burn patients are susceptible to infections due, in part, to immune dysfunction. Upregulation of programmed death-1 (PD-1) receptor on T cells and programmed cell death ligand-1 (PD-L1) on myeloid cells contribute to immune dysfunction in nonburn-related sepsis. We hypothesized that PD-1/PDL1 interactions contribute to immune dysfunction after burn injury. To determine the impact of burn injury and infection on PD-L1, PD-1 and costimulatory receptor expression by leukocytes and its relationship to T cell functions. The efficacy of anti-PD-L1 antibody was evaluated in a clinically relevant mouse model of burn injury and bacterial infection. Mice underwent 35% scald burn followed by Pseudomonas aeruginosa or Staphylococcus aureus infection on day 4 postburn. Anti-PD-L1 was administered on day 3 postburn. Numbers and phenotype of leukocytes, plasma cytokine concentrations, bacterial clearance, organ injury, and survival were assessed. Burn injury and infection with P. aeruginosa caused a significant upregulation of PD-L1 on myeloid cells, along with a decrease in T cell numbers and function, significant multiorgan injury, and decreased survival. Treatment with anti-PD-L1 antibody improved bacterial clearance, reduced organ injury, and enhanced survival during Pseudomonas burn wound infection. Furthermore, anti-PD-L1 effectively protected against multiorgan injury, and improved bacterial clearance and survival following systemic S. aureus infection after burn injury. Blockade of PD-1/PD-L1 interactions might represent a viable treatment to improve outcomes among critically ill burn-injured subjects and increased leukocyte PD-L1 expression could serve as a valuable biomarker to select appropriate patients for such treatment.
烧伤患者易发生感染，部分原因是免疫功能障碍。T 细胞上程序性死亡受体 1（PD-1）和髓样细胞上程序性细胞死亡配体 1（PD-L1）的上调导致非烧伤相关脓毒症中的免疫功能障碍。我们假设 PD-1/PDL1 相互作用导致烧伤后免疫功能障碍。为了确定烧伤和感染对白细胞 PD-L1、PD-1 和共刺激受体表达的影响及其与 T 细胞功能的关系。在烧伤和细菌感染的临床相关小鼠模型中评估了抗 PD-L1 抗体的疗效。小鼠接受 35%的烫伤烧伤，然后在烧伤后第 4 天感染铜绿假单胞菌或金黄色葡萄球菌。在烧伤后第 3 天给予抗 PD-L1 治疗。评估白细胞数量和表型、血浆细胞因子浓度、细菌清除率、器官损伤和存活率。烧伤和铜绿假单胞菌感染导致髓样细胞上 PD-L1 显著上调，同时 T 细胞数量和功能下降，多器官损伤显著，存活率降低。抗 PD-L1 抗体治疗可改善细菌清除率，减轻器官损伤，并提高铜绿假单胞菌烧伤创面感染时的存活率。此外，抗 PD-L1 可有效防止多器官损伤，并改善烧伤后全身性金黄色葡萄球菌感染后的细菌清除率和存活率。阻断 PD-1/PD-L1 相互作用可能是改善严重烧伤患者预后的一种可行治疗方法，增加白细胞 PD-L1 表达可作为选择此类治疗的有价值的生物标志物。
