Tarner Ingo H, Müller-Ladner Ulf, Gay Steffen
Department of Internal Medicine and Rheumatology, Justus-Liebig-University of Giessen, and Division of Rheumatology and Clinical Immunology at the Kerckhoff-Klinik Bad Nauheim, Germany.
Nat Clin Pract Rheumatol. 2007 Jun;3(6):336-45. doi: 10.1038/ncprheum0506.
Advances in molecular biology and the clinical success of strategies that target tumor necrosis factor (TNF) have led to further research into the pathophysiology of human rheumatoid arthritis. Several novel therapeutic targets have emerged from these efforts, including not only molecules that regulate TNF (e.g. TNF-alpha converting enzyme), the complex cytokine network (e.g. interleukin [IL]-6, IL-15, IL-17) and several adipokines, but also targets that originate from cellular and subcellular components of the disease. Strategies that aim at cellular targets include antibodies to CD20 or BLyS (also known as TNF ligand family member 13b), which deplete or inhibit B cells, as well as approaches that interfere with membrane-derived microparticles. Components of subcellular pathways, which are predominantly upstream of the central regulator of transcription nuclear factor kappaB, have also been studied. Of these, strategies that target mitogen-activated protein kinases have a leading role and are on the verge of clinical use; approaches that target specific molecules such as Janus kinases, signal transducer and activator of transcription proteins, and suppressor of cytokine signaling proteins also seem to show promise and might have a clinical application in the future.
分子生物学的进展以及针对肿瘤坏死因子（TNF）策略的临床成功，促使人们对人类类风湿性关节炎的病理生理学进行进一步研究。这些研究产生了几个新的治疗靶点，不仅包括调节TNF的分子（如TNF-α转换酶）、复杂的细胞因子网络（如白细胞介素[IL]-6、IL-15、IL-17）和几种脂肪因子，还包括源自该疾病细胞和亚细胞成分的靶点。针对细胞靶点的策略包括针对CD20或BLyS（也称为TNF配体家族成员13b）的抗体，这些抗体可消耗或抑制B细胞，以及干扰膜衍生微粒的方法。亚细胞途径的成分，主要在转录核因子κB的中央调节因子上游，也已得到研究。其中，针对丝裂原活化蛋白激酶的策略发挥着主导作用，即将投入临床使用；针对特定分子如Janus激酶、信号转导子和转录激活子蛋白以及细胞因子信号传导抑制蛋白的方法似乎也显示出前景，未来可能会有临床应用。
