New therapeutic strategies : a chimeric fusion protein inhibits allergic reactivity

我们已经致力于通过含有免疫受体酪氨酸抑制基序(ITIM)的受体利用负面信号来开发治疗过敏性疾病的新疗法。我们构建了间接将Fcε受体与靶细胞上的FcγII受体偶联的双功能分子，该方法利用由人Fcε和主要猫变应原Fel D1组成的抗原特异性嵌合融合蛋白来共聚集FcγRI和FcγRII。GFD通过直接与Fcγ受体结合，同时通过已经与FcεRI结合的FEL D1抗原特异性Ig E间接与FcεRI结合来阻断介质的释放。GFD被认为是一种更安全的抗原特异性免疫治疗形式，GFD可以阻止对CAT的急性反应，例如不作为过敏原发挥作用，同时仍起到免疫原的作用。在转基因小鼠中，GFD抑制对FELD1的PCA反应，但在致敏部位不诱导皮肤反应。致敏的BALB/c小鼠在第28天和第42天经气管内激发(IT)后，体温下降，肺阻力增加，提示全身和肺部过敏反应。在第7、14和21天皮下注射5μg GFD的小鼠在第28和42天对IT挑战的全身反应性受到抑制。GFD抑制FEL D1诱导的小鼠过敏反应。这个嵌合的伽马过敏原蛋白平台可能提供安全的过敏原特异性治疗，这在食物过敏等情况下可能是至关重要的。

We have undertaken to develop new therapies for allergic diseases by taking advantage of negative signaling via immunoreceptor tyrosine-based inhibition motif (ITIM)-containing receptors. We constructed bi-functional molecules that indirectly crosslink Fcε receptors to the FcγII receptors on targeted cells.This approach employed co-aggregation of FcεRI and FcγRII using an antigen-specific chimeric fusion protein (GFD) that was composed of the human Fcγ and the major cat allergen, Fel d1. GFD was designed to block mediator release by directly attaching to Fcγ receptors and at the same time indirectly binding to FcεRI via Fel d1 antigen specific IgE already bound to FcεRIs. GFD was expected to function as a safer form of antigen specific form of immunotherapy with GFD blocking acute reactivity to cat, e.g. not functioning as an allergen while still functioning as an immunogen.GFD inhibited PCA reactivity to Fel d1 in transgenic mice but did not induce skin reactivity itself at sensitized sites. Balb/c mice sensitized to Fel dl and challenged intratracheally (IT) on day 28 and 42, showed a fall in temperature and increased lung resistance, indicating systemic and pulmonary allergic reactions. Mice given of 5 μg GFD subcutaneously on days 7, 14 and 21 showed inhibition of systemic reactivity to IT challenge at days 28 and 42. GFD inhibited Fel d1-induced allergic response in mice.This chimeric gamma-allergen protein platform may provide allergen-specific therapy with safety profile that may be critical in situations such as food allergy.