FUNCTIONAL ANALYSIS OF PATHOGENIC AND PROTECTIVE PEANUT ALLERGEN-SPECIFIC HUMAN ANTIBODIES

致病性和保护性花生过敏原特异性人类抗体的功能分析

• 批准号: 10331781
• 负责人: Scott Dexter Boyd
• 金额: $ 41.04万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10331781
• 关键词: Affect; Affinity; Aftercare; Allergens; Allergic; Allergic Reaction; Allergy to peanuts; Antibodies; Antigens; B-Lymphocytes; Basophils; Binding; Biological Assay; Biopsy; Biopsy Specimen; Blood; Blood specimen; Calcium; Cell Separation; Cells; Cellular Assay; Clinical; Clone Cells; Development; Diagnostic tests; Disease; Effector Cell; Epitopes; Food; Gastrointestinal tract structure; Gene Rearrangement; Human; Hypersensitivity; IgE; IgG1; IgG4; Immunotherapy; Individual; Knowledge; Lead; Measures; Mediating; Molecular; Monoclonal Antibodies; Morbidity - disease rate; Mucous Membrane; Mutate; Mutation; Pathogenicity; Patients; Phage Display; Prevention; Reaction; Regimen; Research; Sampling; Severities; Severity of illness; Site; Somatic Mutation; Specificity; System; Testing; Therapeutic Trials; Tissues; Tonsil; Variant; cell type; cytokine; desensitization; experimental study; gastrointestinal; human monoclonal antibodies; improved; mast cell; member; mortality; mucosal site; oral immunotherapy; prevent; prognostic assays; receptor; response; treatment response

Food allergic reactions are an increasing cause of morbidity and mortality worldwide, and are triggered by allergen-specific IgE antibodies bound to mast cell and basophil effector cells. The molecular features that make some human IgE antibodies pathogenic have been difficult to study from polyclonal sera that contain mixtures of unknown numbers and proportions of antibody types. Similarly, the mechanisms by which IgG4 and IgG1 antibodies elicited by oral immunotherapy (OIT) can protect patients from allergic reactions would be clarified by studying defined antibodies of known sequence from patients following treatment. We will study the functional activity of defined peanut allergen-specific human IgE, IgG4 and IgG1 monoclonal antibodies (mAbs) isolated from symptomatic allergic patients compared to sensitized but non-allergic controls, and from patients post-treatment who vary in their response to OIT. Cultured primary human mast cells will be used as effector cells, and will be studied with three assays extending from early cell activation (Calcium influx), through effector release, to later cytokine secretion. IgE clones will be evaluated for their allergen specificity, binding affinity, and epitope recognition, and tested in combinations to determine which species can sensitize mast cells. Blocking of mast cell activation by mAb IgG4 and IgG1 will be tested, and Fc mutations used to determine whether Fcγ receptors contribute to decreases in mast cell effector functions. Finally, IgE and other antibody isotypes isolated from patient gastrointestinal tract biopsies will be compared to antibodies isolated from the blood, to determine whether there is enrichment for potentially pathogenic IgE in the mucosal sites where allergic reactions occur. These studies are likely to have a significant impact on basic and translational human allergy research, as they will use a fully human, but well-defined experimental system to identify the molecular features of pathogenic IgE clones in the blood and GI tracts of allergic patients, and evaluate potential IgG4 and IgG1- mediated mechanisms of protection following OIT. Improved understanding of IgE clone affinities, epitope reactivities, and combinations that result in mast cell sensitization could enable better diagnostic and prognostic testing in allergic patients, while more knowledge about the criteria leading to protective IgG4 and IgG1 could guide therapeutic trials and the development of improved immunotherapy regimens.

食物过敏反应是世界范围内发病率和死亡率上升的原因

项目成果

Antibody and B cell responses to SARS-CoV-2 infection and vaccination.

• DOI: 10.1016/j.chom.2021.06.009
• 发表时间: 2021-07-14
• 期刊: Cell host & microbe
• 影响因子: 30.3
• 作者: Röltgen K;Boyd SD
• 通讯作者: Boyd SD

Influenza vaccine-induced human bone marrow plasma cells decline within a year after vaccination.

• DOI: 10.1126/science.aaz8432
• 发表时间: 2020-10-09
• 期刊: SCIENCE
• 影响因子: 56.9
• 作者: Davis, Carl W.;Jackson, Katherine J. L.;McCausland, Megan M.;Darce, Jaime;Chang, Cathy;Linderman, Susanne L.;Chennareddy, Chakravarthy;Gerkin, Rebecca;Brown, Shantoria J.;Wrammert, Jens;Mehta, Aneesh K.;Cheung, Wan Cheung;Boyd, Scott D.;Waller, Edmund K.;Ahmed, Rafi
• 通讯作者: Ahmed, Rafi

Neutrophil-specific gain-of-function mutations in Nlrp3 promote development of cryopyrin-associated periodic syndrome.

• DOI: 10.1084/jem.20201466
• 发表时间: 2021-10-04
• 期刊: The Journal of experimental medicine
• 作者: Stackowicz J;Gaudenzio N;Serhan N;Conde E;Godon O;Marichal T;Starkl P;Balbino B;Roers A;Bruhns P;Jönsson F;Moguelet P;Georgin-Lavialle S;Broderick L;Hoffman HM;Galli SJ;Reber LL
• 通讯作者: Reber LL

Clonal evolution and stereotyped sequences of human IgE lineages in aeroallergen-specific immunotherapy.

空气过敏原特异性免疫治疗中人类 IgE 谱系的克隆进化和定型序列。

• DOI: 10.1016/j.jaci.2023.02.009
• 发表时间: 2023
• 期刊: The Journal of allergy and clinical immunology
• 作者: Hoh,RamonaA;Thörnqvist,Linnea;Yang,Fan;Godzwon,Magdalena;King,JasmineJ;Lee,Ji-Yeun;Greiff,Lennart;Boyd,ScottD;Ohlin,Mats
• 通讯作者: Ohlin,Mats

Genetic variation in the immunoglobulin heavy chain locus shapes the human antibody repertoire.

• DOI: 10.1038/s41467-023-40070-x
• 发表时间: 2023-07-21
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Rodriguez, Oscar L.;Safonova, Yana;Silver, Catherine A.;Shields, Kaitlyn;Gibson, William S.;Kos, Justin T.;Tieri, David;Ke, Hanzhong;Jackson, Katherine J. L.;Boyd, Scott D.;Smith, Melissa L.;Marasco, Wayne A.;Watson, Corey T.
• 通讯作者: Watson, Corey T.