Siglec-targeted nanoparticles for treating mast cell mediated allergic disease

Siglec 靶向纳米颗粒用于治疗肥大细胞介导的过敏性疾病

基本信息

批准号：
10331726
负责人：
JAMES C PAULSON
金额：
$ 50.61万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
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：
2018-02-06 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10331726
关键词：
Affinity Allergens Allergic Disease Anaphylaxis Anti-Allergic Agents Antibodies Antigens Asthma Basophils Binding Bone Marrow CD34 gene Cell Line Cell model Cells Clinical Collaborations Complex Cutaneous Epitopes Fab Immunoglobulins Family Food Haptens Human Hypersensitivity IgE IgE Receptors Immune Sera Immune response In Vitro Ligands Ligation Lipids Liposomes Mediating Modeling Monoclonal Antibodies Mus Passive Cutaneous Anaphylaxis Penicillins Pharmaceutical Preparations Polysaccharides Research Resistance Specificity Symptoms Testing Transgenic Mice Transgenic Model allergic response anti-IgE antigen challenge cross reactivity desensitization design eosinophil experience experimental study humanized mouse immunological synapse improved in vivo mast cell member mouse model nanoparticle novel picric acid receptor recruit response sialic acid binding Ig-like lectin stem cells treatment response

项目摘要

PROJECT SUMMARY/ABSTRACT Unwanted immune responses by mast cells 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 allergen mediated IgE dependent activation and degranulation of human mast cells, and desensitize them to subsequent antigen challenge. To this end we will employ Siglec tolerizing allergenic liposomes (STALs) that display both an allergen and synthetic high affinity glycan ligand of a Siglec expressed on mast cells. When STALs encounter a mast cell pre-sensitized with an allergen specific IgE bound to the high affinity IgE receptor εRI), 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 is hypothesized to recruit the inhibitory Siglec and dampen or suppress activation and degranulation. In this project we will focus on two Siglecs on human mast cells, namely CD33 and Siglec-8. We will assess the impact of STALs for desensitizing human mast cells in models of passive cutaneous and passive systemic anaphylaxis using transgenic mice with mast cells expressing a human Siglec (Siglec-8 and CD33) and a human FcεRI receptor, and humanized mice engrafted with human CD34+ stem cells that populate the mouse with human mast cells. A portion of our effort will also be devoted to improving the specificity of the synthetic ligand for Siglec-8 and develop a novel ligand for the Siglec-6 receptor, a mast cell target for Project 1. (Fc 0

项目概要/摘要肥大细胞的不需要的免疫反应会导致过敏和哮喘的症状。拟议的研究，我们寻求利用抑制性受体 Siglec 家族的成员来抑制过敏原介导人类肥大细胞的 IgE 依赖性激活和脱颗粒，并使它们脱敏为此，我们将使用 Siglec 耐受过敏性脂质体 (STAL)。显示肥大细胞上表达的 Siglec 的过敏原和合成高亲和力聚糖配体。 STAL 遇到肥大细胞，该肥大细胞被与高亲和力 IgE 受体结合的过敏原特异性 IgE 预敏化 εRI)，聚糖配体将招募抑制性 Siglec 至免疫突触，而脂质体则具有。单独的抗原将有力地激活细胞，STAL 上的聚糖配体被寻找以招募抑制性Siglec 和dampcapsulen 或抑制激活和变性在这个项目中我们将重点关注两个。 Siglecs 对人类肥大细胞，即 CD33 和 Siglec-8 我们将评估 STAL 对脱敏的影响。使用转基因小鼠的被动皮肤和被动全身过敏反应模型中的人类肥大细胞肥大细胞表达人 Siglec（Siglec-8 和 CD33）和人 FcεRI 受体，并人源化移植了人类 CD34+ 干细胞的小鼠，这些细胞在小鼠体内填充了人类肥大细胞的一部分。还将致力于提高 Siglec-8 合成配体的特异性，并开发一种新型的 Siglec-6 受体的配体，是项目 1 的肥大细胞靶标。 (Fc 0