New therapeutic strategies : a chimeric fusion protein inhibits allergic reactivity

我们已经着手开发新的治疗过敏性疾病的方法，利用负信号通过免疫受体酪氨酸基抑制基序（ITIM）含有受体。我们构建了一种双功能分子，该分子通过人Fcγ和猫主要过敏原Fel d1的抗原特异性嵌合融合蛋白（GFD），使FcεRI和FcγRII共聚集，从而间接交联靶细胞上的Fcε受体和FcγII受体。GFD被设计为通过直接附着于Fcγ受体并同时通过已结合于Fc ε RI的Fel d1抗原特异性IgE间接结合于Fc ε RI来阻断介质释放。预期GFD作为免疫疗法的抗原特异性形式的更安全形式起作用，其中GFD阻断对猫的急性反应性，例如不作为过敏原起作用，同时仍作为免疫原起作用。GFD抑制转基因小鼠中PCA对Fel d1的反应性，但在致敏部位本身不诱导皮肤反应性。Balb/c小鼠对Fel dl致敏并在第28天和第42天进行气管内（IT）攻击，显示体温下降和肺阻力增加，表明全身和肺过敏反应。在第7、14和21天皮下给予5 μg GFD的小鼠在第28和42天显示出对IT激发的全身反应性抑制。GFD抑制小鼠Fel d1诱导的过敏反应。这种嵌合γ-过敏原蛋白平台可以提供过敏原特异性治疗，其安全性在食物过敏等情况下可能至关重要。

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.