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免疫治疗时代的免疫耐受
Tolerance in the Age of Immunotherapy


Jeffrey A. Bluestone ... 肿瘤 • 2020.09.17

数十年来,诱导和维持有效的免疫耐受一直是免疫学研究的目标。如果免疫系统不再对自身抗原无应答(免疫耐受),失控的免疫应答会导致食物过敏和自身免疫病等疾病。尽管我们于20世纪50年代已经开展了关于免疫耐受的第一项开创性实验1,而且在理解免疫系统基本功能方面取得了进展,但在研发诱导免疫耐受的新型药物过程中却遇到大量临床挑战,罕有药物能够成功诱导持久耐受。但近年来在免疫耐受的基本机制及其维持方面,我们的理解取得了新突破,由此在器官移植、过敏性疾病以及自身免疫病的治疗方面取得了一定成功。此外,新型肽类治疗药物、抗T细胞抗体和细胞疗法为通过短期用药治疗自身免疫病,进而实现长期疗效、避免后续治疗奠定了基础。

在过去数十年间,人们更加深入地了解了与T细胞识别和激活相关的分子事件,从而推动学界研发出多种诱导免疫耐受的方法,如重编程、阻断共刺激信号、检查点抑制以及抗原特异性免疫调节。与免疫耐受相关的术语“免疫无应答”是指机体内无致病性免疫应答(其特征包括免疫细胞失活或缺失),或者指通过调节细胞的参与、细胞分化的偏差或免疫屏障的发育,将致病性免疫应答转化为保护性免疫应答。因此,目前开发免疫耐受药物的方法期望达到下列目标:成功的疗法能够治疗并预防过敏性疾病和自身免疫病,使器官移植和干细胞来源的组织移植无须免疫抑制治疗,以及先天性疾病(如血友病)可以采用蛋白质替代疗法。癌症的免疫耐受有赖于肿瘤特异性的耐受信号和微环境介导的耐受信号;近期取得的治疗成功有许多是通过打破癌症耐受的新型药物。然而,这些治疗药物可能引起自身免疫综合征;这表明,在为了治疗肿瘤而打破免疫耐受与改变全身免疫稳态之间维持微妙平衡极为重要。





作者信息

Jeffrey A. Bluestone, Ph.D., and Mark Anderson, M.D., Ph.D.
From the Sean N. Parker Autoimmune Research Laboratory (J.A.B.) and the Diabetes Center (J.A.B., M.A.), University of California, San Francisco, San Francisco. Address reprint requests to Dr. Bluestone at the UCSF Diabetes Center, 513 Parnassus Ave., Box 0540, San Francisco, CA 94143, or at jeff.bluestone@ucsf.edu.

 

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