结核病宿主导向治疗的研究进展

doi:10.19982/j.issn.1000-6621.20240207

摘要/Abstract

摘要：

宿主导向治疗(host-directed therapy, HDT)是一种新的结核病辅助治疗方法,它针对宿主细胞而非病原体,利用调节宿主免疫应答反应来对抗感染。当药物与抗结核药物联合应用时,有助于增强化学药物疗效、缩短治疗时间、改善免疫病理损伤和减少耐药性产生等。笔者综述了结核病HDT候选药物的常见作用机制,并列举了目前正在研究的HDT候选药物,为寻找新型有效的抗结核治疗药物提供参考依据。

关键词: 结核, 免疫, 治疗应用, 综述文献(主题)

Abstract:

Host-directed therapy (HDT) is a new adjuvant therapy for tuberculosis, which aims at host cells rather than pathogens via modulating host immune response to combat infections. When combined use of HDT with anti-tuberculosis drugs, it provides benefits to enhance the efficacy of chemotherapy, shorten the treatment duration, decrease immunopathological damage, and prevent the emergence of drug resistance. This paper reviews the common mechanisms of HDT, and summarizes several HDT drug candidates that are currently being studied, in order to provide new insight for developing new and effective anti-tuberculosis therapies.

Key words: Tuberculosis, Immunity, Therapeutic uses, Review literature as topic

中图分类号:

闫红璇, 袁金锋, 王艺霖, 逄宇, 高孟秋. 结核病宿主导向治疗的研究进展[J]. 中国防痨杂志, 2024, 46(10): 1273-1282. doi: 10.19982/j.issn.1000-6621.20240207

Yan Hongxuan, Yuan Jinfeng, Wang Yilin, Pang Yu, Gao Mengqiu. Advances in the host-directed therapy of tuberculosis[J]. Chinese Journal of Antituberculosis, 2024, 46(10): 1273-1282. doi: 10.19982/j.issn.1000-6621.20240207

图/表 5

表1

目前正在研究的结核病HDT候选药物

名称	机制	研究阶段	人/动物	参考文献
帕唑帕尼	抑制VEGF,影响肉芽肿	临床前	斑马鱼	[7]
多西环素	抑制MMPs,影响肉芽肿	临床试验Ⅲ期	结核病患者	[8]
伊马替尼	阻断PI3K/Akt/mTOR,促自噬	临床前	小鼠	[9-10]
雷帕霉素	抑制mTOR,促自噬	临床前	小鼠	[11]
依维莫司	抑制mTOR,促自噬	临床试验Ⅱ期	结核病患者	[12]
硝唑尼特	抑制NQO1,促自噬	临床前	细胞	[13]
卡马西平	激活AMPK,促自噬	临床前	小鼠	[14]
氟西汀	促进JNK途径,促自噬	临床前	小鼠	[15]
吉非替尼	抑制p38MAPK,促自噬	临床前	小鼠	[15]
他莫昔芬	促溶酶体输送,促自噬	临床前	斑马鱼	[16]
巴多昔芬	增强ROS产生,促自噬	临床前	细胞	[17]
维生素D3	上调自噬相关基因,促自噬	临床试验Ⅲ期	结核病患者	[18]
维拉帕米	抑制钙离子外排泵Rv1258,促自噬	临床前	细胞	[19-20]
洛哌丁胺	诱导ATG16L1基因的表达,促自噬	临床前	小鼠	[19]
维生素B1	抑制PPAR-γ,增强巨噬细胞杀伤力	临床前	细胞	[21]
霉菌素	抑制PPAR-γ,增强巨噬细胞杀伤力	临床前	小鼠	[22]
二甲双胍	诱导CD8⁺T细胞免疫代谢回路;抑制mTOR,促自噬;调节炎症反应	临床试验Ⅱ期	结核病患者	[23-24]
比阿培南	增强T淋巴细胞对炎症亚群的极化	临床前	小鼠	[25]
氯法齐明	阻断Kv1.3钾通道促进中央记忆型T细胞产生	临床前	小鼠	[11]
沙奎那韦	增加T淋巴细胞的启动和增殖	临床前	细胞	[26]
布洛芬	抑制COX,抑制过度炎症	临床试验Ⅱ期	结核病患者	[27]
阿司匹林	抑制COX,抑制过度炎症	临床试验Ⅱ期	结核病患者	[28]
塞来昔布	抑制COX,抑制过度炎症	临床前	小鼠	[29]
依托考昔	抑制COX,抑制过度炎症	临床试验Ⅰ期	结核病患者	[30]
美洛昔康	抑制COX,抑制过度炎症	临床试验Ⅲ期	结核病患者	[30]
西洛他唑	抑制PDEs,减少巨噬细胞活化和TNF-α表达,抑制过度炎症	临床前	小鼠	[9]
西地那非	抑制PDEs,减少巨噬细胞活化和TNF-α表达,抑制过度炎症	临床前	小鼠	[31]
罗氟司特	抑制PDEs,减少巨噬细胞活化和TNF-α表达,抑制过度炎症	临床前	小鼠	[32]
齐留通	抑制5-LOX,抑制过度炎症	临床前	小鼠	[26]
阿托伐他汀	抑制胆固醇、Rho蛋白合成,抑制过度炎症;诱导自噬	临床试验Ⅱ期	结核病患者	[33-34]
瑞舒伐他汀	抑制胆固醇、Rho蛋白合成,抑制过度炎症;诱导自噬	临床试验Ⅱ期	结核病患者	[33-34]
N-乙酰-L-半胱氨酸乙酯	抑制宿主氧化反应,调节炎症	临床试验Ⅱ期	结核病患者	[35]
舍曲林	抑制Ⅰ型干扰素反应,减轻过度炎症	临床前	小鼠	[36]
依那西普	抑制TNF-α,减轻过度炎症	临床前	小鼠	[37]
托法替尼	抑制JAK,调节炎症	临床前	小鼠	[38]
帕考珠单抗	抗IL-4单克隆抗体,调节炎症	临床试验Ⅱ期	结核病患者	[39]

表1

图1

图2

图3

图4

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