OX40 ligand regulates inflammation and mortality in the innate immune response to sepsis.
OX40 ligand regulates inflammation and mortality in the innate immune response to sepsis.
复制标题
DOI：
10.4049/jimmunol.1000404
复制
发表时间：
2010-10-15
期刊：
影响因子：
--
通讯作者：
Gold JA
中科院分区：
文献类型：
--
作者：
Karulf M;Kelly A;Weinberg AD;Gold JA
脓毒症的初始阶段的特征是大量炎性细胞因子的产生，其导致多系统器官衰竭和死亡。共刺激分子是一类能够在适应性免疫中调节细胞因子产生的受体，最近的研究描述了它们在中性粒细胞和单核细胞上的存在，表明了在先天免疫中调节细胞因子产生的潜在作用。本研究的目的是确定OX 40-OX 40 L相互作用在多微生物脓毒症的先天免疫应答中的作用。脓毒症患者的单核细胞和中性粒细胞上的OX 40 L表达上调，死亡率和ICU停留时间与表达水平相关。在多微生物脓毒症的动物模型中，OX 40 L在调节炎症中的直接作用通过OX 40 L −/−小鼠的存活率提高、细胞因子产生减少和远端器官损伤减少来证明。OX 40 L抗体的类似结果的发现表明OX 40 L阻断在脓毒症中的潜在未来治疗作用。α-OX 40 L无法在巨噬细胞耗竭小鼠中提供显著保护，这使得巨噬细胞成为OX 40/OX 40 L轴内不可或缺的细胞类型，有助于介导脓毒症疾病的临床体征。相反，α-OX 40 L抗体在RAG 1 −/−小鼠中的保护作用进一步证实了OX 40 L刺激在脓毒症中的T细胞非依赖性作用。总之，我们的数据提供了一种新的在体内的作用，OX 40-OX 40 L系统在先天性免疫反应在多微生物脓毒症，并提出了一个潜在的有益的作用，治疗阻断OX 40 L在这种破坏性的疾病。
The initial phase of sepsis is characterized by massive inflammatory cytokine production which contributes to multisystem organ failure and death. Costimulatory molecules are a class of receptors capable of regulating cytokine production in adaptive immunity and recent studies describe their presence on neutrophils and monocytes, suggesting a potential role for regulating cytokine production in innate immunity. The purpose of this study is to determine the role for OX40-OX40L interaction in the innate immune response to polymicrobial sepsis. Humans with sepsis demonstrated upregulation of OX40L on both monocytes and neutrophils, with mortality and ICU stay correlating with expression levels. In an animal model of polymicrobial sepsis, a direct role for OX40L in regulating inflammation was evidenced by improved survival, decreased cytokine production and a decrease in remote organ damage in OX40L−/− mice. The finding of similar results with an OX40L antibody suggests a potential future therapeutic role for OX40L blockade in sepsis. The inability of α-OX40L to provide significant protection in macrophage-depleted mice establishes macrophages as an indispensible cell type within the OX40/OX40L axis that helps to mediate the clinical signs of disease in sepsis. Conversely, the protective effect of α-OX40L antibody in RAG1−/− mice, further confirms a T-cell independent role for OX40L stimulation in sepsis. In conclusion, our data provide a novel in vivo role for OX40-OX40L system in the innate immune response during polymicrobial sepsis and suggests a potential beneficial role for therapeutic blockade of OX40L in this devastating disorder.
登录
查看更多内容
影响因子：
82.9
作者：
Calandra, T;Echtenacher, B;Glauser, MP
通讯作者：
Glauser, MP
影响因子：
4.4
作者：
Lindauer, Meghan L.;Wong, John;Magun, Bruce E.
通讯作者：
Magun, Bruce E.
影响因子：
5.4
作者：
Baumann, R;Yousefi, S;Simon, HU
通讯作者：
Simon, HU
影响因子：
3.9
作者：
Komura, Kazuhiro;Yoshizaki, Ayumi;Sato, Shinichi
通讯作者：
Sato, Shinichi
影响因子：
20.3
作者：
Blazar, BR;Sharpe, AH;Taylor, PA
通讯作者：
Taylor, PA