Chassin Hélène, Geering Barbara, Schukur Lina, Ausländer David, Lang Brian, Fussenegger Martin
Department of Biosystems Science and Engineering, ETH Zürich, Mattenstrasse 26, CH-4058, Basel, Switzerland.
Pharma Research & Early Development, Roche, CH-4070, Basel, Switzerland.
Nat Commun. 2017 Oct 24;8(1):1101. doi: 10.1038/s41467-017-01211-1.
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.
尽管过敏症的患病率持续上升，但在全球范围内，它是慢性病中患病率最高的疾病之一。目前治疗过敏性疾病的方法包括应用抗组胺药、免疫疗法、类固醇和抗免疫球蛋白E（IgE）抗体。在此，我们报告了经过工程改造的哺乳动物细胞，其具有一个合成信号级联，能够监测白细胞介素4和白细胞介素13的细胞外病理生理水平，这两种主要细胞因子共同协调过敏性炎症。当这些细胞因子激活转基因细胞时，一种设计的锚蛋白重复蛋白（DARPin）E2_79（一种结合人IgE的非免疫原性蛋白）以精确控制且可逆的方式分泌。通过人全血细胞培养，我们证明哺乳动物双辅助性T细胞2细胞因子传感器能够产生足够水平的DARPin E2_79，以抑制暴露于过敏原的过敏受试者体内组胺的释放。因此，监测疾病相关细胞因子并结合免疫调节生物制品的原位产生、分泌和全身递送的治疗性基因网络可能会推动过敏症治疗的进展。
