Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio.
Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
J Allergy Clin Immunol. 2022 Feb;149(2):671-684.e9. doi: 10.1016/j.jaci.2021.06.022. Epub 2021 Jun 26.
Administering allergens in increasing doses can temporarily suppress IgE-mediated allergy and anaphylaxis by desensitizing mast cells and basophils; however, allergen administration during desensitization therapy can itself induce allergic responses. Several small molecule drugs and nutraceuticals have been used clinically and experimentally to suppress these allergic responses.
This study sought to optimize drug inhibition of IgE-mediated anaphylaxis.
Several agents were tested individually and in combination for ability to suppress IgE-mediated anaphylaxis in conventional mice, FcεRIα-humanized mice, and reconstituted immunodeficient mice that have human mast cells and basophils. Hypothermia was the readout for anaphylaxis; therapeutic efficacy was measured by degree of inhibition of hypothermia. Serum mouse mast cell protease 1 level was used to measure extent of mast cell degranulation.
Histamine receptor 1 (HR1) antagonists, β-adrenergic agonists, and a spleen tyrosine kinase (Syk) inhibitor were best at individually inhibiting IgE-mediated anaphylaxis. A Bruton's tyrosine kinase (BTK) inhibitor, administered alone, only inhibited hypothermia when FcεRI signaling was suboptimal. Combinations of these agents could completely or nearly completely inhibit IgE-mediated hypothermia in these models. Both Syk and BTK inhibition decreased mast cell degranulation, but only Syk inhibition also blocked desensitization. Many other agents that are used clinically and experimentally had little or no beneficial effect.
Combinations of an HR1 antagonist, a β-adrenergic agonist, and a Syk or a BTK inhibitor protect best against IgE-mediated anaphylaxis, while an HR1 antagonist plus a β-adrenergic agonist ± a BTK antagonist is optimal for inhibiting IgE-mediated anaphylaxis without suppressing desensitization.
通过使肥大细胞和嗜碱性粒细胞脱敏，逐渐增加过敏原剂量的给药可以暂时抑制 IgE 介导的过敏和过敏反应；然而，脱敏治疗期间的过敏原给药本身可以诱导过敏反应。几种小分子药物和营养保健品已在临床上和实验中用于抑制这些过敏反应。
本研究旨在优化药物抑制 IgE 介导的过敏反应。
单独和联合使用几种药物来测试其抑制常规小鼠、FcεRIα 人源化小鼠和重建免疫缺陷小鼠中 IgE 介导的过敏反应的能力。体温过低是过敏反应的读出；治疗效果通过体温过低抑制程度来衡量。血清鼠肥大细胞蛋白酶 1 水平用于测量肥大细胞脱颗粒的程度。
组胺受体 1（HR1）拮抗剂、β-肾上腺素能激动剂和脾酪氨酸激酶（Syk）抑制剂单独使用时最能抑制 IgE 介导的过敏反应。单独给予 Bruton 的酪氨酸激酶（BTK）抑制剂仅在 FcεRI 信号传导不足时抑制体温过低。这些药物的组合可完全或几乎完全抑制这些模型中的 IgE 介导的体温过低。Syk 和 BTK 抑制均可减少肥大细胞脱颗粒，但只有 Syk 抑制也可阻止脱敏。许多其他临床上和实验中使用的药物几乎没有或没有有益效果。
HR1 拮抗剂、β-肾上腺素能激动剂和 Syk 或 BTK 抑制剂的组合可最好地保护免受 IgE 介导的过敏反应，而 HR1 拮抗剂加 β-肾上腺素能激动剂加 BTK 拮抗剂是抑制 IgE 介导的过敏反应而不抑制脱敏的最佳选择。
