Exploiting inhibitory Siglecs for desensitizing mast cells

项目摘要/摘要 肥大细胞和嗜碱性粒细胞的不受欢迎的免疫反应导致过敏和 哮喘。在这项拟议的研究中，我们试图利用Siglec抑制受体家族的成员来 抑制抗原介导的肥大细胞(和嗜碱性粒细胞)的IgE依赖的激活和脱颗粒，以及 使它们对随后的抗原攻击脱敏。为此，我们将使用Siglec耐受抗原 同时显示Mast上表达的Siglec的抗原和高亲和力糖链配体的脂质体(STAL) 细胞。当Stals遇到预先致敏的与高亲和力结合的抗原特异性IgE的肥大细胞时 Ige受体(FcεRI)是一种糖链配体，可将抑制信号募集到免疫突触。而当 仅含抗原的脂质体将有力地激活细胞，Stals上的葡聚糖配体招募 抑制信号阻断活化和脱颗粒。在人类肥大细胞上表达的Siglecs之一是 CD33(Siglec-3)。我们发现Stals共展示抗原和高亲和力的糖链配体CD33可以 抑制肥大细胞脱颗粒的体外实验和表达人CD33-Can基因的转基因小鼠 防止在随后的抗原攻击时发生全身过敏反应。这个项目的主要目标是 CD33靶向抑制IgE介导的致敏小鼠全身过敏反应的优化 模特们。其目标是开发一种方法来提供对抗原介导的过敏反应的持续保护。 免疫球蛋白E/FcεRI轴介导的应答。 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