中国科技论文统计源期刊 中文核心期刊  
美国《化学文摘》《国际药学文摘》
《乌利希期刊指南》
WHO《西太平洋地区医学索引》来源期刊  
日本科学技术振兴机构数据库(JST)
第七届湖北十大名刊提名奖  
医药导报, 2018, 37(8): 952-955
doi: 10.3870/j.issn.1004-0781.2018.08.006
托法替尼的免疫调节作用及临床应用*
李玲, 李作孝

摘要:

自身免疫性疾病发病机制复杂,缺乏疗效确切的治疗药物,患者复发率及病残率极高,探索这类疾病的治疗策略迫在眉睫。托法替尼是一种作用于JAK的新型小分子口服抑制药,其主要通过阻断多种炎症细胞因子的合成和分泌,达到抗炎及调节免疫的作用。迄今为止,该药在治疗类风湿关节炎、银屑病、炎症性肠病、肾移植排斥反应、多发性硬化等疾病方面效果肯定。随着托法替尼在免疫性疾病中作用机制的深入研究,有望将托法替尼作为治疗更多免疫性疾病新的靶向药物。

关键词: 托法替尼 ; 自身免疫性疾病 ; 免疫调节作用 ; 临床应用

Abstract:

托法替尼(tofacitinib)是一种作用于JAK的新型小分子口服抑制药,由美国食品药品管理局(FDA)于2012年11月批准用于成人的中度至重度活动性类风湿性关节炎(rheumatoid arthritis,RA)的治疗。研究显示,目前除RA外,托法替尼在银屑病、炎症性肠病、肾移植排斥反应、多发性硬化等多种免疫性疾病的治疗中也取得了满意的治疗效果。笔者就托法替尼的免疫调节作用及临床应用综述如下。

1 托法替尼的免疫调节作用
1.1 JAK-STAT信号转导通路的作用

JAK-STAT信号转导通路是许多关键性细胞因子发挥作用的重要信号通路,与细胞的增殖、分化、凋亡及免疫调节等病理生理过程有着密切关系。该信号通路主要由酪氨酸激酶相关受体、JAK和 STAT组成,其中JAK 的激活在介导自身免疫性疾病中炎性因子的产生和免疫细胞的活化方面发挥着重要作用[1]。JAK家族主要包括JAK1、JAK2、JAK3 及Tyk2四个重要成员,其中JAK1、JAK2和Tyk2广泛分布于人体内各组织、细胞中,在机体生长、神经系统发育和造血方面发挥调节作用,而JAK3存在于骨髓和淋巴系统中,参与机体的免疫应答[2]。研究发现多种细胞因子均可激活JAK-STAT信号转导通路,如干扰素(IFN)家族、共同γ链(γC)、糖蛋白130(gp130)家族等。上述细胞因子与靶细胞上相应受体结合后,可使JAK磷酸化,从而促使STAT磷酸化,激活JAK-STAT信号通路发挥调节转录的功能。JAK-STAT信号转导通路在类风湿性关节炎、银屑病、炎症性肠病、肾移植排斥反应及多发性硬化等多种疾病的发病过程中起到至关重要的作用,因此该通路已成为多种疾病特别是自身免疫性疾病的治疗靶目标[3]

1.2 托法替尼的免疫调节机制

托法替尼化学名称为3-((3R,4R)-4-甲基-3-(甲基(7H-吡咯并[2,3-d] 嘧啶-4-基) 氨基) 哌啶-1-基)-3-氧代丙腈,2-羟基丙烷-1,2,3-三羧酸(1:1)。分子式C16H20N6O;分子量312.37。托法替尼以细胞内JAK-STAT信号转导通路为靶点,通过抑制JAK磷酸化,从而阻止STAT磷酸化,使下游炎症细胞因子合成减少,进而抑制C D 4 + T细胞增殖,阻断多种炎症细胞因子的合成和分泌,达到抗炎、调节免疫的作用。研究发现,托法替尼可阻断与JAK3结合的共同γC链细胞因子(IL-2,IL-7,IL-9,IL-15 和IL-21等),同时还可阻断gp130家族(IL-6 和 IL-11)及Ⅱ型细胞因子受体家族(IFN-α/β,IFN-γ等)。由于该药对JAK2也有相对较弱的抑制作用,故亦可阻断βc家族(IL-3,IL-5,GM-CSF,EPO和IFN-γ)[4]。由此可见,托法替尼能够通过阻断JAK1和JAK2来影响Th1细胞的分化及致病性Th17细胞的产生。此外,由于托法替尼对IL-21有阻断作用,推测其可能对B细胞及滤泡辅助性T细胞(Tfh细胞)的功能产生影响[5]。MASANORI等[6]研究发现,除了抑制细胞免疫应答,托法替尼还能通过调节体液免疫发挥作用。该药可以通过有效抑制抗原特异性抗体反应,进而影响生发中心(germinal center,GC)形成、抑制B细胞和T细胞分化增殖及Ig类别转换,并在一定程度降低血清总IgG水平,从而抑制体液免疫反应。

2 托法替尼的临床应用
2.1 治疗类风湿关节炎

类风湿关节炎是一种以滑膜组织炎性增生关节软骨进行性破坏为主要特征的慢性炎症性自身免疫性疾病。研究表明,JAK-STAT信号通路在RA 患者的滑膜组织中高表达,对RA的发病起到重要作用[7]。托法替尼以细胞内JAK-STAT信号转导通路为靶点,通过抑制JAK磷酸化,从而阻止STAT磷酸化,使下游炎症细胞因子合成减少,阻断IL-2、IL-6、IL-7、IL-17、IL-21、IFN-γ等多种细胞因子的合成和分泌,从而抑制C D 4 + T细胞增殖和其他炎症细胞的募集,缓解了RA 患者滑膜的炎症和关节破坏,改善了RA患者的临床症状。目前多项临床试验已证实了托法替尼在治疗RA方面的有效性及安全性。在1项为期6个月的临床试验中,610例对抗风湿药物(disease-modifying antirheumatic drugs,DMARDs)治疗反应不佳的RA 患者接受了托法替尼(5 mg或10 mg,口服,每天2次)或先服用安慰药3个月再加用托法替尼治疗[8]。托法替尼治疗后健康评估问卷残疾指数HAQ-DI评价情况明显改善、ACR20反应率明显升高,疾病活动度评分显著改善[9]。另外,在一项由国内20家医院参与的为期12个月的国际多中心、随机双盲、安慰药对照临床试验中,共纳入了792 例DMARDs治疗反应不佳的中度到重度活动性RA患者,随机分为3组,分别给予托法替尼5,10 mg及安慰药[10]。实验结果显示,托法替尼可以明显改善对DMARD 治疗反应不佳的活动性RA 患者的病情、提高ACR20反应率,并且随剂量的增加,ACR70反应率升高时间提前。LEE等[11]开展的Ⅲ期临床试验进一步证实了托法替尼单一治疗效果要优于甲氨蝶呤,有望成为治疗RA新的一线药物。

2.2 治疗银屑病

银屑病(psoriasis)是一种多基因遗传背景下免疫失衡介导的慢性炎症性疾病,该病以T细胞、树突状细胞、巨噬细胞、自然杀伤细胞、中性粒细胞等炎症细胞浸润为特点[12,13]。研究表明,致炎因子IL-15在银屑病皮肤病损部位高表达,并能诱导抗凋亡角质细胞产生。作为JAK抑制药,托法替尼能够通过阻断JAK-STAT信号转导通路,进一步抑制包括IL-15在内的多种细胞因子的产生,对银屑病病情的缓解起到重要作用[14,15]。目前托法替尼在患有严重慢性斑块性银屑病的成人患者中进行的5项Ⅲ期临床实验中,2项已取得成功,分别是口服治疗银屑病比较研究(OPT Compare,A3921080) 和口服治疗银屑病复治研究(OPT Retreatment,A3921111)。与对照组比较,托法替尼组达到银屑病面积和严重性指数(psoriasis area and severity index,PASI) 下降75%及医师全球评估指标(physician's global assessment,PGA) 响应达“清除”或“几乎清除”的患者比例明显增多,表明托法替尼可显著缓解银屑病患者病情[16,17]

2.3 治疗炎症性肠病

炎症性肠病(inflammatory bo-wel disease,IBD) 是一组累及肠道的慢性非特异性炎症疾病,包括溃疡性结肠炎(ulcerative colitis,UC)和克罗恩病(Crohn’s disease,CD)。其发病机制尚未完全明了,目前认为与遗传、环境、微生物感染及免疫等多项因素有关,其中,免疫学机制在IBD的发病中占有重要地位。多项研究结果显示,JAK1、JAK3及JAK-STAT信号转导通路在IBD的发生发展中起着重要作用。在一项为期8周的Ⅱ期临床试验中,给予中至重度UC患者托法替尼治疗,治疗组患者对药物的临床反应、临床缓解、肠黏膜修复情况均优于对照组,C-反应蛋白(CRP)和粪便钙卫蛋白浓度较对照组明显降低[18]。另外,在一项为期4周的Ⅱ期临床试验中,给予中至重度CD患者托法替尼治疗,与对照组比较,托法替尼治疗组的CRP和粪便钙卫蛋白浓度也明显降低[19]。以上实验均提示托法替尼对IBD的治疗具有潜在的应用价值,但仍需进行更多、更大规模的临床研究来进一步验证托法替尼治疗IBD的有效性。

2.4 治疗肾移植排斥反应

慢性肾脏病(chronic kidney disease,CKD) 及终末期肾病(end-stage renal disease,ESRD) 发病率逐年上升,病死率和致残率高。目前肾移植已成为治疗ESRD的有效手段。但肾移植后出现的急性排斥反应会影响移植肾的长期存活,因而肾移植术后免疫抑制药的应用对移植肾的存活起到重要作用。研究显示,环孢素(CsA)、他克莫司、西罗莫司及霉酚酸酯等常见的免疫抑制药可对抗钙调神经磷酸酶抑制药介导的功能性肾损伤及移植肾的组织病理学异常[20,21]。VINCENTI等[22]通过一项Ⅱ期临床试验(NCT00483756)发现,在肾移植患者中,托法替尼是对抗钙调神经磷酸酶抑制药的主要药物[23,24],与环孢素相比,托法替尼可降低急性排异反应,保护肾功能,减少间质慢性纤维化及肾小管上皮细胞萎缩的发生率,并且可降低移植后新发糖尿病的比率。

2.5 治疗多发性硬化

多发性硬化(multiple sclerosis,MS)是一种以中枢神经系统炎性脱髓鞘为特点的自身免疫性疾病,实验性自身免疫性脑脊髓炎(experimental allergic encephalomyelitis,EAE)是公认研究MS的理想动物模型。MS的发病机制目前尚不明确。研究证实,多条细胞内信号传导通路异常参与了MS的发病过程,其中JAK-STAT信号转导通路异常与 MS关系尤为密切[25]。YIN等[26]研究发现,EAE大鼠发病高峰期脑组织中JAK-STAT信号转导通路关键蛋白磷酸化明显增加; 抑制JAK-STAT信号通路蛋白磷酸化能够明显降低EAE大鼠的发病率、延缓疾病发展,改善神经功能障碍。同时,ZHOU等[27]研究还发现,新型JAK抑制药托法替尼可通过产生耐受性树突状细胞(tolerogenic DCs,tolDCs)来改善EAE病情的进展。BENVENISTE等[25]提出托法替尼有望成为MS新的有效治疗方式。

3 结束语

作为JAK 抑制药,托法替尼通过抑制JAK磷酸化,从而抑制STAT磷酸化,阻断JAK-STAT信号转导通路,进一步抑制下游多种炎症因子的产生及T细胞、B细胞的活化,下调机体免疫应答,多项临床及临床前研究证实其对类风湿性关节炎、银屑病、炎症性肠病、肾移植排斥反应及多发性硬化均有明显治疗作用。由此可见,随着托法替尼在免疫性疾病中抗炎及免疫调节作用、疗效及安全性、耐药及个体化治疗靶点的进一步研究与探讨,有望将托法替尼作为治疗更多免疫性疾病新的靶向药物。

The authors have declared that no competing interests exist.

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Natural killer (NK) cells are large, granular lymphocytes devoted to the defense against microbial agents and cancer cells, traditionally recognized as an important arm of the innate immunity, even if more recent data underpin a role also in the responses of acquired immunity. Several studies have led to ascertain that NK cells are involved in the pathogenesis of many immune-mediated diseases, where they may exert both protective and pathogenic roles. In particular, the CD56bright NK cell subset, showing immunoregulatory properties, has been found to accumulate in tissue sites of inflammation, such as the skin lesions in psoriatic patients and the synovial membrane in rheumatoid arthritis (RA) patients. In this latter disease, while data on the number of NK cells are still controversial among the different studies, more consensuses exist on the impaired activity of these cells. In another group of inflammatory arthritides, the spondyloarthropathies (SpA), the presence of peculiar allotypes of the killer cell immunoglobulin-like receptors (KIR) superfamily, coding for molecules expressed on NK cells, seems to modulate the susceptibility to this group of diseases, especially ankylosing spondylitis and psoriatic arthritis. Interestingly, in vitro studies showed that NK cells of patients with inflammatory arthropathies might produce pro-inflammatory Th1 cytokines; furthermore, they are involved in bone damage, interact and activate different cell types such as monocytes, dendritic cells and resident fibroblast-like synoviocites cells, thus creating and/or maintaining the inflammatory response. Certainly, these features encourage more research on the role of NK cells in the pathogenesis of inflammatory arthropathies, which could be essential to define potential new therapeutic strategies.
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Protein kinases play a crucial role in the intracellular signaling pathways involved in inflammation and cell proliferation. Advances in our understanding of these metabolic pathways and of the role played by intracellular signaling in the pathogenesis of psoriasis have led to research in this area and the development of a new class of drugs for the treatment of psoriasis and other inflammatory processes. Since kinase inhibitors are small molecules, oral and topical treatments are possible. The future role of these molecules in the therapeutic arsenal used to treat psoriasis is as yet unknown because in most cases they are still in the early stages of research. The fact that these drugs may cost much less than biologic therapies could favor their approval in coming years. Tofacitinib, a Janus kinase inhibitor, is the drug that has reached the most advanced stage of research and has shown the most promising results.
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Keratinocytes (KC) are important source of and targets for several cytokines. Although KC express mRNA, the functional effects of on these epithelial remain to be dissected. Investigating primary foreskin KC and HaCaT , we show here by semiquantitative RT-PCR and flow cytometric analysis that both translate and IL-15R mRNA and express and on the , suggesting that KC can employ for juxtacrine . While exerted no significant effect on KC proliferation and or , inhibited both anti-and -induced KC apoptosis in vitro. This is in line with the recognized potent anti-apoptotic effects of . , whose receptor shares two components with the IL-15R, failed to inhibit KC apoptosis. Together with the role of in sustaining chronic immune reactions, this invited the question of whether a reduction of KC apoptosis by may be involved in the of , a chronic hyperproliferative inflammatory characterized by abnormally low KC apoptosis in the epidermis. Remarkably, compared with nonlesional psoriatic skin and skin of healthy volunteers, lesional psoriatic epidermis showed high expression in the epidermis and enhanced activity for . Therefore, antagonizing the inhibitory effects of on KC apoptosis deserves exploration as a novel therapeutic strategy in management.
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Janus kinase (JAK) pathways are key mediators in the immunopathogenesis of psoriasis. Psoriasis treatment has evolved with the advent of targeted therapies, which inhibit specific components of the psoriasis proinflammatory cascade. JAK inhibitors have been studied in early phase trials for psoriasis patients, and the data are promising for these agents as potential treatment options. Tofacitinib, an oral or topically administered JAK1 and JAK3 inhibitor, and ruxolitinib, a topical JAK1 and JAK2 inhibitor, have been most extensively studied in psoriasis, and both improved clinical symptoms of psoriasis. Additional JAK1 or JAK3 inhibitors are being studied in clinical trials. In phase III trials for rheumatoid arthritis, tofacitinib was efficacious in patients with inadequate responses to tumor necrosis factor inhibitors, methotrexate monotherapy, or disease-modifying antirheumatic drugs. The results of phase III trials are pending for these therapies in psoriasis, and these agents may represent important alternatives for patients with inadequate responses to currently available agents. Further investigations with long-term clinical trials are necessary to verify their utility in psoriasis treatment and assess their safety in this patient population.
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Clinical Pharmacology & Therapeutics, the most cited journal publishing primary investigation in pharmacology and pharmacy, is the authoritative, cross-disciplinary journal in experimental and clinical medicine devoted to publishing advances in the nature, action, efficacy and evaluation of therapeutics.
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Tofacitinib fixed-dose regimens attained better kidney function and comparable efficacy to cyclosporine (CsA) in kidney transplant patients, albeit with increased risks of certain adverse events. This post-hoc analysis evaluated whether a patient subgroup with an acceptable risk-benefit profile could be identified. Tofacitinib exposure was a statistically significant predictor of serious infection rate. One-hundred and eighty six kidney transplant patients were re-categorized to above-median (AME) or below-median (BME) exposure groups. The 6-month biopsy-proven acute rejection rates in AME, BME and CsA groups were 7.8%, 15.7% and 17.7%, respectively. Measured glomerular filtration rate was higher in AME and BME groups versus CsA (61.2 and 67.9 vs. 53.9L/min) at Month 12. Fewer patients developed interstitial fibrosis and tubular atrophy (IF/TA) at Month 12 in AME (20.5%) and BME (27.8%) groups versus CsA (48.3%). Serious infections occurred more frequently in the AME group (53.0%) than in BME (28.4%) or CsA (25.5%) groups. Posttransplant lymphoproliferative disorder (PTLD) only occurred in the AME group. In kidney transplant patients, the BME group preserved the clinical advantage of comparable acute rejection rates, improved renal function and a lower incidence of IF/TA versus CsA, and with similar rates of serious infection and no PTLD.
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托法替尼
自身免疫性疾病
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李玲
李作孝