Cytos Biotechnology AG, Zurich-Schlieren, Switzerland.
J Allergy Clin Immunol. 2010 Aug;126(2):375-83. doi: 10.1016/j.jaci.2010.05.040. Epub 2010 Jul 10.
Allergen-specific desensitization (SIT) is the most effective therapy for allergies. Although allergen-specific antibodies have an important role in the process, mechanisms of IgG-mediated inhibition of allergic reactions are not well defined.
We investigated mechanisms by which SIT-induced allergen-specific IgGs inhibit allergic reactions.
We generated mAbs that recognize 3 nonoverlapping epitopes of the major cat allergen Fel d 1. Each of the mAbs was produced as an IgE and different IgG isotype.
IgEs against 2 nonoverlapping epitopes on Fel d 1 are necessary and sufficient to sensitize mast cells for maximal FcepsilonRI signaling and degranulation on exposure to monomeric Fel d 1. IgE antibodies of a third specificity did not further increase mast cell degranulation, indicating that formation of large FcepsilonRI clusters are not required to induce maximal activation of mast cells. A single IgG that was specific for an epitope different from those recognized by the IgEs was a potent inhibitor of Fel d 1-mediated mast cell activation in vitro and in vivo. This inhibition required Fcgamma receptor-IIB. In human beings, IgGs of a single specificity were able to block degranulation of basophils from individuals with cat allergy. The inhibitory potential of these antibodies increased when larger allergen-IgG complexes were formed.
These data reconcile conflicting theories in the literature and might explain the reason IgE levels do not necessarily decrease during therapy, despite clinical efficacy. These findings have important implications for vaccine design.
变应原特异性脱敏（SIT）是治疗过敏最有效的方法。尽管过敏原特异性抗体在该过程中具有重要作用，但 IgG 介导的抑制过敏反应的机制尚不清楚。
我们研究了 SIT 诱导的过敏原特异性 IgG 抑制过敏反应的机制。
我们生成了识别主要猫过敏原 Fel d 1 的 3 个非重叠表位的 mAb。每种 mAb 均作为 IgE 和不同的 IgG 同种型产生。
针对 Fel d 1 上的 2 个非重叠表位的 IgE 是致敏肥大细胞的必要和充分条件，可使其在暴露于单体 Fel d 1 时最大程度地激活 FcepsilonRI 信号和脱颗粒。第三种特异性的 IgE 抗体不会进一步增加肥大细胞脱颗粒，表明形成大的 FcepsilonRI 簇不是诱导肥大细胞最大激活所必需的。与 IgE 识别的表位不同的单一 IgG 特异性是体外和体内 Fel d 1 介导的肥大细胞激活的有效抑制剂。这种抑制需要 Fcgamma 受体-IIB。在人类中，来自猫过敏个体的单一特异性 IgG 能够阻断嗜碱性粒细胞的脱颗粒。当形成更大的过敏原-IgG 复合物时，这些抗体的抑制潜力增加。
这些数据调和了文献中的冲突理论，并可能解释了为什么尽管临床疗效显著，但在治疗过程中 IgE 水平不一定会降低的原因。这些发现对疫苗设计具有重要意义。
