Reprogramming of B cells into regulatory cells with engineered fusokines.
Reprogramming of B cells into regulatory cells with engineered fusokines.
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DOI：
10.2174/187152612800564392
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发表时间：
2012-06
期刊：
影响因子：
--
通讯作者：
Galipeau J
中科院分区：
文献类型：
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作者：
Deng J;Galipeau J
B细胞在宿主对病原微生物的获得性免疫中起着关键作用，但也可能在自身免疫性疾病的发病机制中起着不良的作用。相比之下，不同的B细胞亚群具有调节宿主免疫反应和抑制炎症的能力。B调节细胞是一种罕见的内源性B淋巴细胞，部分由抗炎细胞因子IL-10的产生决定。尽管体内存在“天然的”B调节细胞，但B调节细胞的低频率可能是它们在自身免疫性疾病中影响的一个限制因素。为了满足这一未得到满足的需求，我们开发了一种替代淋巴激活的新策略：纤毛素。这些完全工程化的嵌合亮氨酸融合了两个功能无关的细胞因子，以实现交替免疫调节的目的。由GM-CSF和IL-15衍生的Fusokine：GIFT15，通过IL15受体介导具有全新的和未知的免疫调节特性，将幼稚的B细胞重新编程为B调节细胞(Bregs)。在这篇文章中，我们回顾了目前在体外产生Bregs的方法，并强调了GIFT15诱导Bregs在小鼠中取消病理性自身免疫的功能获得机制。我们还证明了人类可诱导Bregs的等价物也可能成为治疗自身免疫性疾病的一种新的有效治疗工具。
B cells play a pivotal role in host adaptive immunity against pathogenic microorganisms, but may also maladaptively contribute to the pathogenesis of autoimmune diseases. In contrast, distinct B cell subsets have the capacity to regulate host immune response, and suppress inflammation. B regulatory cells are a rare population of endogenous B-lymphocytes defined in part by production of the anti-inflammatory cytokine IL-10. Although “natural” B regulatory cells exist in vivo, the low frequency of B regulatory cells may be a limiting factor on their impact in autoimmune ailments. In answer to this unmet need, we have developed a novel strategy for alternate lymphoid activation: fusokines. These wholly engineered chimeric leukines fuse two functionally unrelated cytokines for the purpose of alternate immune modulation. The GM-CSF- and IL-15-derived fusokine: GIFT15, possesses entirely novel and unheralded immune modulating properties mediated through the IL15 receptor which reprograms naïve B cells into B regulatory cells (Bregs). In this article, we review the current approaches to generate Bregs in vitro, and highlight gain-of-function mechanisms by which GIFT15-induced Bregs abrogate pathogenic autoimmunity in mice. We also demonstrate that the human equivalent of inducible Bregs may also serve as a new potent therapeutic tool for treatment of autoimmune disease.