National Institute of Arthritis, Musculoskeletal and Skin Diseases, Molecular Immunology and Inflammation Branch, National Institutes of Health, Bethesda, Maryland, USA.
J Leukoc Biol. 2018 Sep;104(3):499-514. doi: 10.1002/JLB.5RI0218-084R. Epub 2018 Jul 12.
In this era, it is axiomatic that cytokines have critical roles in cellular development and differentiation, immune homeostasis, and host defense. Equally, dysregulation of cytokines is known to contribute to diverse inflammatory and immune-mediated disorders. In fact, the past 20 years have witnessed the rapid translation of basic discoveries in cytokine biology to multiple successful biological agents (mAbs and recombinant fusion proteins) that target cytokines. These targeted therapies have not only fundamentally changed the face of multiple immune-mediated diseases but have also unequivocally established the role of specific cytokines in human disease; cytokine biologists have many times over provided remarkable basic advances with direct clinical benefit. Numerous cytokines rely on the JAK-STAT pathway for signaling, and new, safe, and effective small molecule inhibitors have been developed for a range of disorders. In this review, we will briefly summarize basic discoveries in cytokine signaling and briefly comment on some major unresolved issues. We will review clinical data pertaining to the first generation of JAK inhibitors and their clinical indications, discuss additional opportunities for targeting this pathway, and lay out some of the challenges that lie ahead.
在这个时代，细胞因子在细胞发育和分化、免疫稳态和宿主防御中起着至关重要的作用，这是不言而喻的。同样，细胞因子的失调也被认为是导致多种炎症和免疫介导性疾病的原因。事实上，在过去的 20 年里，细胞因子生物学的基础发现已经迅速转化为多种成功的生物制剂（单克隆抗体和重组融合蛋白），这些生物制剂针对细胞因子。这些靶向治疗不仅从根本上改变了多种免疫介导性疾病的面貌，而且明确确立了特定细胞因子在人类疾病中的作用；细胞因子生物学家多次提供了具有直接临床益处的显著基础进展。许多细胞因子依赖 JAK-STAT 途径进行信号传递，并且已经开发出了一系列用于多种疾病的新型、安全和有效的小分子抑制剂。在这篇综述中，我们将简要总结细胞因子信号转导的基础发现，并简要评论一些尚未解决的主要问题。我们将回顾第一代 JAK 抑制剂的临床数据及其临床适应证，讨论靶向该途径的其他机会，并阐述未来面临的一些挑战。
