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Exploiting inhibitory Siglecs for desensitizing mast cells

利用抑制性 Siglecs 使肥大细胞脱敏

基本信息

批准号：
10219077
负责人：
JAMES C PAULSON
金额：
$ 61.27万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-24 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10219077
关键词：
Affinity Allergens Anaphylaxis Anti-Allergic Agents Antibodies Antigens Asthma Basophils Binding Caring Cell Degranulation Cells Cessation of life Complex Development Dose Epitopes Extrinsic asthma Family Goals Human Hypersensitivity IgE IgE Receptors IgG1 IgG4 Immune response Immunization Immunoglobulin G Immunologic Tests Immunotherapy In Vitro Interleukin 4 Receptor Lead Ligands Liposomes Mediating Modeling Monitor Mus Oral Ovalbumin Passive Cutaneous Anaphylaxis Patients Pharmaceutical Preparations Polysaccharides Process Production Regimen Regulatory T-Lymphocyte Research Serum Symptoms System Testing Time Transgenic Mice Work allergic response anti-IgE antigen challenge base desensitization food allergen immunological synapse mast cell member mouse model mutant novel novel strategies omalizumab passive sensitization prevent receptor recruit response sialic acid binding Ig-like lectin

项目摘要

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

项目总结/文摘