Dominant-negative inhibitors of soluble TNF attenuate experimental arthritis without suppressing innate immunity to infection
Dominant-negative inhibitors of soluble TNF attenuate experimental arthritis without suppressing innate immunity to infection
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DOI：
10.4049/jimmunol.179.3.1872
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发表时间：
2007-08-01
影响因子：
4.4
通讯作者：
Szymkowski, David E.
中科院分区：
文献类型：
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作者：
Zalevsky, Jonathan;Secher, Thomas;Szymkowski, David E.
TNF是免疫系统正常发育和功能所需的多效性细胞因子;然而，TNF过表达也诱导炎症并与自身免疫性疾病相关。TNF以可溶性和跨膜蛋白的形式存在。小鼠遗传研究表明，疾病模型中的炎症涉及可溶性TNF（solTNF），而先天免疫功能的维持涉及跨膜TNF（tmTNF）。这些发现意味着选择性药理学抑制solTNF可能是抗炎的，但仍保留对感染的先天免疫。为了解决这一假设，我们现在将TNF的显性负性抑制剂（DN-TNFs）描述为选择性抑制solTNF的一类新的生物制剂。DN-TNF阻断人和小鼠细胞中的solTNF活性，人血液细胞因子释放测定和两种小鼠关节炎模型。相反，DN-TNF既不抑制人或小鼠tmTNF的活性，也不抑制小鼠对李斯特菌感染的先天免疫。这些结果确立了DN-TNF作为solTNF的第一选择性抑制剂，证明小鼠关节炎模型中的炎症主要由solTNF驱动，并表明tmTNF活性的维持可改善未来抗炎剂的治疗指数。
TNF is a pleiotropic cytokine required for normal development and function of the immune system; however, TNF overexpression also induces inflammation and is associated with autoimmune diseases. TNF exists as both a soluble and a transmembrane protein. Genetic studies in mice have suggested that inflammation in disease models involves soluble TNF (solTNF) and that maintenance of innate immune function involves transmembrane TNF (tmTNF). These findings imply that selective pharmacologic inhibition of solTNF may be anti-inflammatory and yet preserve innate immunity to infection. To address this hypothesis, we now describe dominant-negative inhibitors of TNF (DN-TNFs) as a new class of biologics that selectively inhibits solTNF. DN-TNFs blocked solTNF activity in human and mouse cells, a human blood cytokine release assay, and two mouse arthritis models. In contrast, DN-TNFs neither inhibited the activity of human or mouse tmTNF nor suppressed innate immunity to Listeria infection in mice. These results establish DN-TNFs as the first selective inhibitors of solTNF, demonstrate that inflammation in mouse arthritis models is primarily driven by solTNF, and suggest that the maintenance of tmTNF activity may improve the therapeutic index of future anti-inflammatory agents.