Siglec-targeted nanoparticles for treating mast cell mediated allergic disease

项目摘要/摘要 肥大细胞不想要的免疫反应会导致过敏和哮喘的症状。在 我们试图利用抑制性受体Siglec家族成员抑制的拟议研究 变应原介导的人肥大细胞的IgE依赖的激活和脱颗粒，并使其对 随后的抗原挑战。为此，我们将使用Siglec耐受性过敏性脂质体(Stals) 展示在肥大细胞上表达的Siglec的过敏原和合成的高亲和力多糖配体。什么时候 Stals遇到预先致敏的肥大细胞，该肥大细胞与高亲和力IgE受体结合的过敏原特异性IgE εRI)，多糖配体会将抑制信号征募到免疫突触。而脂质体与 抗原本身就会强大地激活细胞，STALL上的多糖配体被认为是为了招募 抑制信号，抑制或抑制激活和脱颗粒。在这个项目中，我们将重点介绍两个 人肥大细胞上的Siglecs，即CD33和Siglec-8。我们将评估STALS对脱敏的影响 利用转基因小鼠建立被动皮肤和被动全身过敏反应模型中的人肥大细胞 用表达人Siglec(Siglec-8和CD33)和人FcεRI受体的肥大细胞，并人源化 植入人类CD34+干细胞的小鼠体内植入了人类肥大细胞。我们的一部分 还将致力于提高Siglec-8的合成配体的特异性，并开发一种新的 Siglec-6受体的配体，项目1的肥大细胞靶点。 (功能界别 0

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