Sensing and responding to allergic response cytokines through a genetically encoded circuit.
Sensing and responding to allergic response cytokines through a genetically encoded circuit.
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DOI：
10.1038/s41467-017-01211-1
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发表时间：
2017-10-24
影响因子：
16.6
通讯作者：
Fussenegger M
中科院分区：
文献类型：
--
作者：
Chassin H;Geering B;Schukur L;Ausländer D;Lang B;Fussenegger M
虽然过敏症的患病率不断上升，但在全球慢性疾病中，过敏症的患病率是最高的之一。目前过敏性疾病的治疗方法包括应用抗组胺药物、免疫疗法、类固醇和抗免疫球蛋白E(IgE)抗体。在这里，我们报告了具有合成信号级联的哺乳动物细胞能够监测细胞外白介素4和白介素13的病理生理水平，这两种主要细胞因子协调变态反应性炎症。当这些细胞因子激活转基因细胞时，设计的锚蛋白重复蛋白(DARPin)E2_79是一种非免疫原性结合人IgE的蛋白，以精确控制和可逆的方式分泌。利用人类全血细胞培养，我们证明哺乳动物Dual T Helper 2细胞因子传感器产生足够水平的DARPin E2_79，以抑制暴露于过敏原的过敏性受试者的组胺释放。因此，监测疾病相关细胞因子的治疗性基因网络与免疫调节生物制剂的原位生产、分泌和系统递送相结合，可能会促进过敏治疗的进展。过敏反应的标准治疗方法是抗组胺、类固醇和抗IgE抗体。在这里，作者提出了一种感知IL-4和IL-13的遗传电路，并通过产生DARPin来反应结合IgE。
While constantly rising, the prevalence of allergies is globally one of the highest among chronic diseases. Current treatments of allergic diseases include the application of anti-histamines, immunotherapy, steroids, and anti-immunoglobulin E (IgE) antibodies. Here we report mammalian cells engineered with a synthetic signaling cascade able to monitor extracellular pathophysiological levels of interleukin 4 and interleukin 13, two main cytokines orchestrating allergic inflammation. Upon activation of transgenic cells by these cytokines, designed ankyrin repeat protein (DARPin) E2_79, a non-immunogenic protein binding human IgE, is secreted in a precisely controlled and reversible manner. Using human whole blood cell culturing, we demonstrate that the mammalian dual T helper 2 cytokine sensor produces sufficient levels of DARPin E2_79 to dampen histamine release in allergic subjects exposed to allergens. Hence, therapeutic gene networks monitoring disease-associated cytokines coupled with in situ production, secretion and systemic delivery of immunomodulatory biologics may foster advances in the treatment of allergies. The standard treatment for an allergic response is anti-histamines, steroids and anti-IgE antibodies. Here the authors present a genetic circuit that senses IL-4 and IL-13 and responses with DARPin production to bind IgE.
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影响因子：
12.4
作者：
Howarth, PH;Salagean, M;Dokic, D
通讯作者：
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14.2
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通讯作者：
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