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：
10097996
负责人：
JAMES C PAULSON
金额：
$ 53.21万
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 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10097996
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

项目摘要/摘要肥大细胞不需要的免疫反应有助于过敏和哮喘的符号。在提议的研究我们寻求利用Siglec抑制受体家族的成员抑制过敏原介导的IgE依赖性激活和人类肥大细胞的脱粒，并使它们脱敏随后的抗原挑战。为此，我们将采用Siglec耐受过敏性脂质体（Stals）同时显示在肥大细胞上表达的Siglec的过敏原和合成高亲和力配体。什么时候 Stals遇到具有过敏原特异性IgE的肥大细胞，与高亲和力接收器结合 εri），聚糖配体将使抑制性Siglec募集到免疫突触。而脂质体与仅抗原将有力地激活细胞，假设固醇上的聚糖配体可以募集抑制性siglec和抑制或抑制激活和脱粒。在这个项目中，我们将重点关注两个人类肥大细胞的SIGLEC，即CD33和SIGLEC-8。我们将评估Stals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模型中的人类肥大细胞用表达人Siglec（Siglec-8和CD33）和人FcεRI受体的肥大细胞和人源化与人CD34+干细胞一起植入了用人肥大细胞填充小鼠的小鼠。我们的一部分努力也将致力于提高SIGLEC-8的合成配体的特异性并开发新颖 SIGLEC-6受体的配体，项目1的肥大细胞靶标。（FC 0