PI3K signalling in B- and T-lymphocytes: new developments and therapeutic advances.
PI3K signalling in B- and T-lymphocytes: new developments and therapeutic advances.
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DOI：
10.1042/bj20112092
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发表时间：
2012-03-15
期刊：
影响因子：
--
通讯作者：
Fruman DA
中科院分区：
文献类型：
--
作者：
So L;Fruman DA
磷酸肌醇3-激酶（PI 3 K）的激活是对不同类型跨膜受体参与的共同反应。根据细胞类型和刺激，PI 3 K活化可以促进不同的命运，包括增殖、存活、迁移和分化。PI 3 K信号传导的不同作用通过对淋巴细胞（介导适应性免疫的细胞）的研究得到了很好的说明。遗传和药理学实验已经表明，PI 3 K活化调节B和T细胞的发育、活化和分化中的许多步骤。这些发现促进了PI 3 K抑制剂用于治疗自身免疫和炎性疾病的发展。然而，PI 3 K激活在免疫系统激活中具有积极和消极的作用。因此，虽然PI 3 K抑制可以减弱免疫应答，但它也可以增强炎症，破坏外周耐受性并促进自身免疫。一个令人兴奋的发现是PI 3 K的p110δ催化亚型的选择性抑制剂CAL-101在某些B细胞恶性肿瘤中实现了令人印象深刻的临床疗效。一种模型正在出现，其中p110δ抑制破坏来自淋巴微环境的信号，导致白血病和淋巴瘤细胞从其保护性生态位释放。这些令人鼓舞的发现为PI 3 K药物在癌症和免疫疾病中的开发工作提供了进一步的动力。
Activation of phosphoinositide 3-kinase (PI3K) is a shared response to engagement of diverse types of transmembrane receptors. Depending on the cell type and stimulus, PI3K activation can promote different fates including proliferation, survival, migration and differentiation. The diverse roles of PI3K signaling are well illustrated by studies of lymphocytes, the cells that mediate adaptive immunity. Genetic and pharmacological experiments have shown that PI3K activation regulates many steps in the development, activation and differentiation of both B and T cells. These findings have prompted the development of PI3K inhibitors for the treatment of autoimmunity and inflammatory diseases. However, PI3K activation has both positive and negative roles in immune system activation. Consequently, while PI3K suppression can attenuate immune responses it can also enhance inflammation, disrupt peripheral tolerance and promote autoimmunity. An exciting discovery is that a selective inhibitor of the p110δ catalytic isoform of PI3K, CAL-101, achieves impressive clinical efficacy in certain B cell malignancies. A model is emerging in which p110δ inhibition disrupts signals from the lymphoid microenvironment, leading to release of leukemia and lymphoma cells from their protective niche. These encouraging findings have given further momentum to PI3K drug development efforts in both cancer and immune diseases.