How self-tolerance and the immunosuppressive drug FK506 prevent B-cell mitogenesis
How self-tolerance and the immunosuppressive drug FK506 prevent B-cell mitogenesis
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DOI：
10.1038/35001102
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发表时间：
2000-02-10
期刊：
影响因子：
64.8
通讯作者：
Mack, DH
中科院分区：
文献类型：
--
作者：
Glynne, R;Akkaraju, S;Mack, DH
移植排斥、自身免疫性疾病和过敏的治疗必须针对在发育过程中逃脱审查的成熟淋巴细胞。 FK506 和环孢菌素是免疫抑制剂，通过抑制钙调神经磷酸酶 (1) 阻断三种抗原受体信号通路（NFAT、NF kappa B 和 JNK），并抑制成熟淋巴细胞向抗原增殖 (2-4)。然而，这两种药物都不会在体内诱导长期耐受，因此需要长期使用，并产生不良副作用。外周对自身抗原耐受的生理机制提供了在药理学上模拟这些过程的机会。在这里，我们使用基因表达阵列为外周 B 细胞无反应性中促有丝分裂反应的丧失提供分子解释，这是免疫耐受性的一个方面(5)。自身抗原诱导一组基因，其中包括信号传导和转录的负调节因子，但不包括促进增殖的基因。 FK506 干扰耐受反应的钙依赖性成分，并阻止一小部分激活反应。许多以前与自我耐受无关的基因被揭示，我们的研究结果为开发改进的免疫抑制剂提供了分子指纹，这些免疫抑制剂可防止淋巴细胞激活而不阻断外周耐受。
Therapy for transplant rejection, autoimmune disease and allergy must target mature lymphocytes that have escaped censoring during their development. FK506 and cyclosporin are immunosuppressants which block three antigen-receptor signalling pathways (NFAT, NF kappa B and JNK), through inhibition of calcineurin(1), and inhibit mature lymphocyte proliferation to antigen(2-4) Neither drug induces long-lived tolerance in vivo, however, necessitating chronic use with adverse side effects. Physiological mechanisms of peripheral tolerance to self-antigens provide an opportunity to emulate these processes pharmacologically. Here we use gene-expression arrays to provide a molecular explanation for the loss of mitogenic response in peripheral B-cell anergy, one aspect of immunological tolerance(5). Self-antigen induces a set of genes that includes negative regulators of signalling and transcription but not genes that promote proliferation. FK506 interferes with calcium-dependent components of the tolerance response and blocks an unexpectedly small fraction of the activation response. Many genes that were not previously connected to self-tolerance are revealed, and our findings provide a molecular fingerprint for the development of improved immunosuppressants that prevent lymphocyte activation without blocking peripheral tolerance.