Blood:锌能够促进骨髓移植后免疫系统的再生和恢复

2022-04-16 王聪 “生物世界”公众号

胸腺是 T 淋巴细胞发育的主要部位,T 细胞的恢复依赖于胸腺组织再生,但胸腺的修复和再生能力会随年龄的增长而减少。增强胸腺修复和再生能力对于恢复免疫系统有重大临床意义,但目前还没有获批的治疗方法。

对于癌症患者而言,无论是接受化疗,还是骨髓移植、细胞治疗,都会面临长时间的淋巴细胞减少症状,这会导致他们出现感染和癌症复发的风险。

胸腺是 T 淋巴细胞发育的主要部位,T 细胞的恢复依赖于胸腺组织再生,但胸腺的修复和再生能力会随年龄的增长而减少。增强胸腺修复和再生能力对于恢复免疫系统有重大临床意义,但目前还没有获批的治疗方法。

锌(Zinc)是公认的增强人体免疫力的微量元素,之前的研究也表明锌可以促进接受干细胞移植的癌症患者的免疫系统的恢复,但锌究竟是如何发挥这以作用的尚不清楚。

近日,美国弗雷德哈钦森癌症研究中心的 Jarrod Dudakov 等人在 Blood 期刊发表了题为:Activation of the Zinc-sensing receptor GPR39 promotes T cell reconstitution after hematopoietic cell transplant in mice 的研究论文。

该研究发现,锌对于正常的 T 细胞发育和损伤后修复至关重要,而且还通过促进胸腺再生来促进 T 细胞的产生。该研究进一步揭示了,在造血干细胞移植后,胸腺细胞中积累的锌会释放到细胞外环境中,通过细胞表面受体 GPR39 刺激内皮细胞产生再生因子 BMP4,从而促进胸腺组织再生。

通过膳食补充锌,能够促进造血干细胞移植后的小鼠的胸腺再生和功能恢复,研究团队进一步证实,使用小分子激动剂直接靶向 GPR39,可以直接增强胸腺再生和功能恢复,且效果好于补充锌。

总的来说,该研究增加了我们对锌在免疫系统中的实际作用的了解,定义了组织再生的新途径,还提供了一种创新方法来促进造血干细胞移植后患者的免疫系统重建。

在此之前,Jarrod Dudakov 团队已经研究了调控免疫系统胸腺的自我修复的分子机制和细胞类型。这些研究有助于提高疫苗的效果,并在化疗、细胞治疗、辐射暴露等之后加速胸腺再生,促进免疫系统恢复。

之前的研究已经表明,低水平的锌与 T 细胞减少和胸腺萎缩有关。而且补充锌可以促进那些接受干细胞移植的多发性骨髓瘤患者的免疫系统恢复。但尚不清楚锌是如何发挥这些作用的。

锌对 T 细胞发育和胸腺再生至关重要

在这项最新研究中,研究团队发现,在短短三周的无锌饮食后,小鼠的胸腺会萎缩,且显着减少了成熟 T 细胞的产生,也就是锌的缺乏会导致 T 细胞不能发育成熟。他们还发现,在免疫系统破坏的小鼠中,缺乏锌会减缓 T 细胞数量的恢复,相反,补充锌会加速其恢复,且恢复速度超过正常速度。在造血干细胞移植小鼠中,他们观察到了类似的结果。

基于上述发现,研究团队得出结论,补充锌后,凶险的到了更好地重建,外周血中的 T 细胞也得到了更好地重建。但锌究竟是如何发挥这些功能的还不明朗。

研究团队进一步发现,当破坏性事件发生后(例如放疗、造血干细胞移植前的清髓),胸腺细胞会释放之前积累的锌,细胞表面受体 GPR39 会感知细胞外锌水平的变化,刺激内皮细胞产生再生因子 BMP4,从而促进胸腺组织再生。

研究团队表示,平时通过饮食摄入的锌会在胸腺细胞和发育中的 T 细胞中积累并储存,一旦出现破坏性事件,这些细胞中的锌被释放到细胞外,导致细胞外锌水平升高,从而触发胸腺再生。

而通过小分子激动剂直接靶向激活 GPR39,能够立即启动胸腺组织再生,促进 T 细胞重建,效果好于通过饮食补充锌。

临床转化

进行造血干细胞移植的癌症患者,已经接受了矿物质补充剂,如果在他们的治疗方案中加入额外的锌,首先要确定他们是否真的缺锌。该论文的第一作者 Lorenzo Iovino 认为,大多数患者是缺锌的,但目前还没有很好的标准来测试这一点。

因此,他们正在开发一种方法来确定患者是否缺锌,并将用来确认患者的锌状态是否与造血干细胞移植后的免疫系统恢复有关。他们还在筛选刺激 GPR39 的化合物,用于促进治疗后的胸腺再生和免疫系统重建。

此外,随着年龄的增长,人们的胸腺会逐渐萎缩并减少 T 细胞的输出,这项研究也有望用于减慢年龄相关的免疫系统退化。

锌含量最高的食物

原始出处:

Lorenzo Iovino, Kirsten Cooper, Paul deRoos, et al. Activation of the Zinc-sensing receptor GPR39 promotes T cell reconstitution after hematopoietic cell transplant in mice. Blood, 2021013950.

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    2022-08-20 小小医者

    #锌#能够促进#骨髓移植#后免疫系统的#再生#和恢复

    0

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    2022-04-30 杨海东

    坚持学习

    0

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    2022-04-27 杨海东

    坚持学习

    0

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    2022-04-22 杨海东

    坚持学习

    0

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    2022-04-19 杨海东

    学习学习

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