Siglec-targeted nanoparticles for treating mast cell mediated allergic disease

项目总结/摘要 肥大细胞产生的不必要的免疫反应会导致过敏和哮喘的症状。在 我们提出的研究旨在利用Siglec家族的抑制性受体来抑制 过敏原介导的IgE依赖性人肥大细胞的活化和脱粒，并使它们对 随后抗原激发。为此，我们将采用Siglec耐受过敏性脂质体（STAL）， 展示过敏原和在肥大细胞上表达的Siglec的合成高亲和力聚糖配体两者。当 STAL遇到了用与高亲和力IgE受体结合的过敏原特异性IgE预致敏的肥大细胞 εRI）时，聚糖配体将募集抑制性Siglec至免疫突触。而脂质体与 抗原单独将有力地激活细胞，STAL上的聚糖配体被假设为募集抗原。 抑制Siglec并抑制或抑制活化和脱粒。在这个项目中，我们将重点关注两个 人肥大细胞上的Siglec，即CD 33和Siglec-8。我们将评估STAL对脱敏的影响， 人肥大细胞在转基因小鼠被动皮肤和被动全身过敏反应模型中作用 与表达人Siglec（Siglec-8和CD 33）和人FcεRI受体的肥大细胞接触，并人源化 移植有人CD 34+干细胞的小鼠，所述干细胞使小鼠充满人肥大细胞。或类似的交易 还将致力于改善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，Siglec-6受体是项目1的肥大细胞靶标。 （Fc） 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