First Department of Propedeutic and Internal Medicine, Athens University Medical School, Greece.
Clin Immunol. 2011 Dec;141(3):231-5. doi: 10.1016/j.clim.2011.09.005. Epub 2011 Sep 16.
Although pivotal to the immune system homeostasis, tumor necrosis factor (TNF) becomes deleterious when de-regulated. The currently marketed TNF blockers are highly efficacious in rheumatoid arthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, uveitis and inflammatory bowel disease; reactivation of tuberculosis and exacerbation of pre-existing multiple sclerosis remain their most important safety issues. The endogenous protein progranulin binds TNF receptor-1 (TNFR1) and TNFR2, thus blocking their interactions with TNF. Domains of the extracellular region of TNFR, termed preligand-binding assembly domain (PLAD), mediate receptor-chain trimerization which is essential for signaling. Therapeutic administration of either progranulin or soluble versions of TNFR1 PLAD in mouse models of diseases in which TNF is relevant yielded beneficial results, opening the door to the next generation of non-antibody anti-TNF drugs for a variety of non-infectious inflammatory conditions. Whether these drugs may target TNF in a more refined way than the current blockers, perhaps being more efficacious without compromising the protective role of TNF in host defense and (auto)immunity, remains to be seen.
虽然肿瘤坏死因子 (TNF) 在免疫系统稳态中起着关键作用，但当其失调时就会变得有害。目前市场上的 TNF 阻滞剂在类风湿关节炎、强直性脊柱炎、银屑病、银屑病关节炎、虹膜炎和炎症性肠病中非常有效；结核病的再激活和先前存在的多发性硬化症的恶化仍然是它们最重要的安全问题。内源性蛋白颗粒蛋白结合 TNF 受体-1（TNFR1）和 TNFR2，从而阻断它们与 TNF 的相互作用。TNFR 细胞外区域的结构域，称为前配体结合组装域 (PLAD)，介导受体链三聚体化，这对于信号转导是必需的。在 TNF 相关疾病的小鼠模型中，给予颗粒蛋白或 TNFR1 PLAD 的可溶性版本进行治疗，产生了有益的结果，为下一代非抗体抗 TNF 药物治疗各种非传染性炎症疾病开辟了道路。这些药物是否可以比目前的阻滞剂更精细地靶向 TNF，也许在不损害 TNF 在宿主防御和（自身）免疫中的保护作用的情况下更有效，还有待观察。
