Exploiting inhibitory Siglecs for desensitizing mast cells

项目总结/摘要 肥大细胞和嗜碱性粒细胞引起的不必要的免疫应答有助于过敏症状， 哮喘在拟议的研究中，我们试图利用抑制性受体的Siglec家族的成员， 抑制肥大细胞（和嗜碱性粒细胞）抗原介导的IgE依赖性活化和脱粒，和 使它们对随后的抗原攻击脱敏。为此，我们将采用Siglec耐受性抗原 脂质体（STAL），其展示在肥大细胞上表达的Siglec的抗原和高亲和力聚糖配体 细胞当STAL遇到用抗原特异性IgE预致敏的肥大细胞时， 免疫球蛋白E受体（FcεRI）是一种聚糖配体，它将抑制性siglec募集到免疫突触。而 脂质体与抗原单独将有力地激活细胞，STAL上的聚糖配体招募细胞， 抑制性siglec阻断活化和脱粒。在人肥大细胞上表达的Siglecs之一是 CD33（Siglec-3）。我们已经发现，共展示抗原和高亲和力聚糖配体CD 33的STAL可以 在体外和在具有表达人CD 33肥大细胞的转基因小鼠中抑制肥大细胞脱颗粒， 在随后的抗原攻击时防止全身过敏反应。该项目的主要目标是 在致敏小鼠中优化CD 33靶向STAL以抑制IgE介导的全身过敏反应 模型目的是开发一种方法，提供持续的保护，防止抗原介导的过敏反应， IgE/FcεRI轴介导的免疫应答。 0

PROJECT SUMMARY/ABSTRACT Unwanted immune responses by mast cells and basophils contribute to the symptoms of allergies and asthma. In the proposed research we seek to harness members of the Siglec family of inhibitory receptors to suppress antigen mediated IgE dependent activation and degranulation of mast cells (and basophils), and desensitize them to subsequent antigen challenge. To this end we will employ Siglec tolerizing antigenic liposomes (STALs) that display both an antigen and high affinity glycan ligand of a Siglec expressed on mast cells. When STALs encounter a mast cell pre-sensitized with antigen specific IgE bound to the high affinity IgE receptor (FcεRI), the glycan ligand will recruit the inhibitory siglec to the immunological synapse. While liposomes with antigen alone will powerfully activate the cells, the glycan ligand on STALs recruits the inhibitory siglec blocking activation and degranulation. One of the Siglecs expressed on human mast cells is CD33 (Siglec-3). We have found that STALs co-displaying antigen and high affinity glycan ligands CD33 can suppress mast cell degranulation in vitro and in transgenic mice with mast cells expressing human CD33 can protect against systemic anaphylaxis upon subsequent antigen challenge. Major aims of this project are to optimize CD33 targeted STALs for suppressing IgE mediated systemic anaphylaxis, in sensitized mouse models. The goal is to develop an approach to provide sustained protection against antigen mediated allergic responses mediated by the IgE/FcεRI axis. 0