在接受JAK抑制剂治疗的RA年轻患者中,NK细胞细胞毒性显著降低
Takahiko Akagi1,2, Yasumitsu Nishimura3, Shunichi Fujita1
1Department of Rheumatology, Kawasaki Medical School, Kurashiki, Okayama, Japan.
Rheumatology (Oxford, England)
|June 5, 2025
概括
简氏激酶抑制剂 (JAKi) 显著降低自然杀手 (NK) 细胞活性,并在类风湿性关节炎 (RA) 患者中改变其表型. 年龄较小和使用葡萄糖皮质激素是JAKi患者NK细胞功能下降的危险因素.
科学领域:
- 免疫学 免疫学 免疫学
- 类风湿病学 类风湿病学
- 药理学 药理学是指药理学的学科.
背景情况:
- 简氏激酶抑制剂 (JAKi) 是对类风湿性关节炎 (RA) 的有效治疗方法,可以实现低疾病活性 (LDA).
- 临床前数据表明,JAKi可能会影响自然杀手 (NK) 细胞功能,引发人们对感染和恶性瘤风险的担忧.
- 在RA患者中,JAKi对NK细胞的特定作用尚未完全理解.
研究的目的:
- 研究JAK抑制剂 (JAKi) 对RA患者NK细胞活性和表型的影响.
- 在接受JAKi治疗的RA患者中比较NK细胞活性与TNF抑制剂 (TNFi).
- 确定与治疗RA患者NK细胞活性降低相关的风险因素.
主要方法:
- 在接受JAKi (n=85) 或TNFi (n=131) 治疗的RA患者中,使用51Cr释放试验测量了周围血液NK细胞的细胞毒性活性.
- 使用倾向分数匹配来控制混变量.
- 流细胞计被用来评估NK细胞成熟和分化标志物.
主要成果:
- 与TNFi组相比,JAKi组的NK细胞活性明显较低 (中位数为50%与36%,P=0.002).
- JAKi治疗与NK和CD56dim细胞的比例降低,CD56bright细胞的比例增加有关.
- 在JAKi组中,使用葡萄糖皮质激素 (OR 5.36) 和年龄较小 (<50岁;OR 10.56) 是减少NK细胞活性的独立风险因素. 在较年轻的RA患者 (<50岁) 中,疹发病率较高,NK细胞活性较低.
结论:
- 在RA患者中,使用JAK抑制剂治疗显著损害NK细胞活性和分化.
- 患者年龄和同时使用葡萄糖皮质激素影响了JAKi对NK细胞功能的影响.
- 这些发现突出了与RA中JAKi治疗相关的潜在安全问题,特别是关于年轻患者感染风险.
相关概念视频
The JAK-STAT Signaling Pathway
12.2K
Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as SH2...
12.2K
Drugs for Treatment of Crohn's Disease in IBD Using Immunomodulatory Agents
495
Crohn's disease is an inflammatory bowel disorder marked by chronic inflammation of the GI tract. Various treatment strategies for Crohn's disease are employed, such as immunomodulatory agents, glucocorticoids, and biologics or anti-TNF therapy. Azathioprine (Imuran), a commonly used immunomodulatory drug for Crohn's disease, is converted in the body to mercaptopurine, which inhibits purine biosynthesis and cell proliferation. Both are utilized in severe cases of Inflammatory Bowel...
495
Drugs for Treatment of Crohn's Disease in IBD Using Biologic Agents: Anti-TNF
506
Tumor Necrosis Factor (TNF), a proinflammatory cytokine, contributes significantly to the inflammation seen in Crohn's disease. It exists as soluble TNF and membrane-bound TNF, with actions mediated through TNF receptors (TNFR). TNFR activation leads to the release of proinflammatory cytokines, T-cell activation, collagen production, and leukocyte migration, all contributing to inflammation in Crohn's disease. Anti-TNF monoclonal antibodies, namely infliximab (Remicade), adalimumab...
506
T Cell Types and Functions
2.2K
When T cells with CD4 markers are activated, they give rise to two types of effector cells: helper T cells and regulatory T cells. Meanwhile, T cells with CD8 markers differentiate into effector cytotoxic T cells. The differentiation of CD4 T cells into helper T cell subsets, such as Th1, Th2, and Th17 cells, is dependent on the antigen type, antigen-presenting cell, and regulatory cytokines.
Th1 cells stimulate dendritic cells to express necessary co-stimulatory molecules on their surfaces for...
Th1 cells stimulate dendritic cells to express necessary co-stimulatory molecules on their surfaces for...
2.2K
Receptor Downregulation in MVBs
2.8K
Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR...
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR...
2.8K
Cytotoxic T Cells-mediated Immune Response
6.5K
Cytotoxic T cells are a vital component of the immune system. They have the remarkable ability to identify and target antigens on infected or abnormal cells. These antigens often originate from intracellular pathogens such as viruses or abnormal proteins cancer cells produce.
Immunological surveillance is the ability of immune cells to monitor and eliminate infected cells with intracellular pathogens, neoplastically transformed cells, and cells with non-self antigens. Cytotoxic T cells and NK...
Immunological surveillance is the ability of immune cells to monitor and eliminate infected cells with intracellular pathogens, neoplastically transformed cells, and cells with non-self antigens. Cytotoxic T cells and NK...
6.5K


