CXCL10 and Soluble Programmed Death-Ligand 1 during Respiratory Viral Infections Are Associated with Chronic Lung Allograft Dysfunction in Lung Transplant Recipients.
CXCL10 and Soluble Programmed Death-Ligand 1 during Respiratory Viral Infections Are Associated with Chronic Lung Allograft Dysfunction in Lung Transplant Recipients.
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呼吸道病毒感染期间的 CXCL10 和可溶性程序性死亡配体 1 与肺移植受者的慢性同种异体肺移植功能障碍有关。
DOI：
10.1165/rcmb.2021-0404le
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发表时间：
2022
影响因子：
6.4
通讯作者：
Lease,Er
中科院分区：
文献类型：
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作者：
Morrell,EricD;Brager,Carolyn;Ramos,KathleenJ;Chai,Xin-Ya;Kapnadak,SiddharthaG;Edelman,Jeffrey;Matute-Bello,Gustavo;Altemeier,WilliamA;Hwang,Billanna;Mulligan,MichaelS;Bhatraju,PavanK;Wurfel,MarkM;Mikacenic,Carmen;Lease,Er
慢性肺移植功能障碍(CLAD)在肺移植(LTX)受者中有一半在移植后5年发生，并且是第一年后死亡的主要原因(1)。呼吸道病毒感染(RVI)是CLAD(2-8)最重要的流行病学危险因素之一，但RVI与CLAD之间的宿主免疫学机制尚不清楚。干扰素-g和干扰素刺激的介质CXCL10和程序性死亡配体1(PD-L1)在正常宿主对RVI的反应中起着关键作用。呼吸道和肺泡上皮细胞在RVI刺激下分泌干扰素-γ。CXCL10(趋化因子)和PD-L1(检查点蛋白)均高度上调抗原提呈细胞对干扰素-g(9，10)的反应。CXCL10有助于将激活的T细胞招募到炎症部位，患者在RVI时BAL液中CXCL10的浓度较高，与感染后6个月1秒内的用力呼气量显著降低有关(10)。PD-L1是一种检查点蛋白，通过抑制T细胞活性来调节炎症。PD-L1/PD-1通路已被证明在小鼠肺移植耐受中起关键作用(11)，并且有多种现有的治疗方法来调节这一通路(12)。PD-L1诱导和维持调节性T细胞，这与随后的CLAD的发展有关(13)。可溶性PD-L1(Spd-L1)以前没有在LTX接受者的临床队列中被检测到，但最近被证明在体外可以减少T细胞的增殖。通过外周血样本测量循环宿主对RVI的免疫反应，有可能阐明RVI和CLAD之间的系统联系，并且与支气管镜检查相比，是一种更安全、更容易进行临床分析的采样方法(10)。我们对那些在RVI或急性细胞排斥(ACR)(没有RVI)时采集血液的LTX接受者进行了一项回顾性队列研究，并测试了免疫介质浓度与随后的临床结果之间的关系。我们假设血液中的干扰素刺激的介质与RVI后CLAD的发生有关。我们分析了从2007年1月至2012年5月在华盛顿大学接受首次LTX的250名连续成年患者的样本。该队列中所有在RVI诊断前7天内或RVI诊断后2天内(阳性试验结果的日期)收集的现存血清的参与者被纳入RVI组。对于ACR组，如果他们有ACR的发作(因原因进行的经支气管镜活检至少A1级或B1级组织学排斥反应)(15)，并且在分析期间没有合并RVI，则参与者符合条件。临床结果评估直到RVI或ACR后1年(2)。这项研究得到了华盛顿大学机构审查委员会的批准。
Chronic lung allograft dysfunction (CLAD) develops in half of lung transplant (LTx) recipients by 5 years post-transplantation and is the primary cause of death after the first year (1). Respiratory viral infections (RVIs) are among the most important epidemiologic risk factors for CLAD (2-8), but the host immunologic mechanisms linking RVI with CLAD are unclear. IFN-g and the IFN-stimulated mediators CXCL10 and programmed death-ligand 1 (PD-L1) play a key role in the normal host response to RVIs. Airway and alveolar epithelial cells secrete IFN-g in response to RVI. CXCL10 (chemokine) and PD-L1 (checkpoint protein) are both highly upregulated on antigen-presenting cells in response to IFN-g (9, 10). CXCL10 helps recruit activated T cells to sites of inflammation, and higher concentrations of CXCL10 in the BAL fluid of patients at the time of RVI are associated with significantly lower forced expiratory volume in 1 second at 6 months postinfection (10). PD-L1 is a checkpoint protein that regulates inflammation by suppressing T cell activity. The PD-L1/PD-1 pathway has been shown to play a key role in lung allograft tolerance in mice (11), and there are multiple existing therapies that modulate this pathway (12). PD-L1 induces and maintains regulatory T cells, which have been associated with subsequent development of CLAD (13). Soluble PD-L1 (sPD-L1) has not been previously measured in a clinical cohort of LTx recipients but has recently been shown to reduce T cell proliferation in vitro (14). Measurement of the circulating host immune response to RVI through peripheral blood samples offers the potential to elucidate the systemic links between RVI and CLAD and is a safer and easier sampling approach for clinical assays compared with bronchoscopy (10). We conducted a retrospective cohort study of LTx recipients who had blood collected at the time of RVI or acute cellular rejection (ACR)(without RVI) and tested for associations between immune mediator concentrations and subsequent clinical outcomes. We hypothesized that IFN-stimulated mediators in the blood are associated with the development of CLAD following RVI.We analyzed samples from a cohort of 250 consecutive adult patients who received their first LTx between January 2007 and May 2012 at the University of Washington (2). All participants within this cohort who had extant serum that was collected within 7 days before or up to 2 days after the diagnosis of RVI (date of the positive test result) were included in the RVI group. For the ACR group, participants were eligible if they had episodes of ACR (at least A1-or B1-grade histologic rejection on transbronchial biopsies performed for cause)(15) and did not have coexisting RVIs during the analysis time. Clinical outcomes were assessed until 1 year after RVI or ACR (2). This study was approved by the University of Washington institutional review board.