Exploiting inhibitory Siglecs for desensitizing mast cells

利用抑制性 Siglecs 使肥大细胞脱敏

• 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
• 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

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