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Regulation of germinal centers by thymic stromal lymphopoietin in mice and humans

胸腺基质淋巴细胞生成素对小鼠和人类生发中心的调节

基本信息

批准号：
10442512
负责人：
Phillip P Domeier
金额：
$ 7.17万
依托单位：
BENAROYA RESEARCH INST AT VIRGINIA MASON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10442512
关键词：
Affect Affinity Allergens Allergic Disease Anaphylaxis Antibodies Antibody Affinity Antibody Formation Antibody Response Antibody Specificity Antibody-Producing Cells Antigens B cell differentiation B-Cell Development B-Lymphocyte Differentiation Antigens B-Lymphocytes Blocking Antibodies CD4 Positive T Lymphocytes Cat allergy Cells Coculture Techniques Complement 3d Receptors Data Developed Countries Development Event Felis catus Follicular Dendritic Cells Foundations Frequencies Helper-Inducer T-Lymphocyte Human Hypersensitivity IL4 gene IgE IgG1 Immune Immune response Immunity Immunization Immunize Immunoglobulin Class Switching In Vitro Interleukin-13 Literature LoxP-flanked allele Maintenance Mature B-Lymphocyte Measures Mediating Mus Mutation Parasites Parasitic infection Pathogenicity Patients Peripheral Peripheral Blood Mononuclear Cell Plasma Cells Play Population Prevalence Production Proteins Receptor Gene Receptor Signaling Regulation Research Role Signal Transduction Source Specificity Structure Structure of germinal center of lymph node Surface System T-Lymphocyte TSLP gene Tamoxifen Testing Training Work aluminum sulfate base curative treatments cytokine experimental study follow-up in vivo mortality mouse model new therapeutic target novel novel therapeutics ovalbumin-alum prevent receptor receptor expression response secondary lymphoid organ

项目摘要

PROJECT SUMMARY IgE antibodies to environmental proteins are detected in up to 40% of the worldwide population, and the prevalence of allergic disease continues to rise in industrialized nations. Although several therapies can mitigate antibody-driven anaphylaxis or block antibody effector functions, high mortality rates persist without a curative treatment, and the mechanisms that control allergen-specific antibody production are still poorly understood. Previous work from our group and others showed that Thymic Stromal Lymphopoietin (TSLP) is required for the development allergic disease, and we recently discovered that TSLP also plays an additional role in controlling IgE and IgG1 antibody production in germinal centers (GCs). GC B cells and T follicular helper cells upregulate the expression of surface TSLP receptor (TSLPR) as they enter into the GC microenvironment, and TSLPR- deficient mice produce significantly lower titers of antigen-specific IgG1 and IgE upon immunization. When CD4+ T cells specifically lack TSLPR expression (CD4creTSLPRF/F), immunized mice develop similar frequencies of antigen-specific germinal centers, but lower numbers of IgG1-producing B cells with high-affinity for antigen, suggesting that TSLPR expression on T cells may be required for affinity maturation in the germinal center. Therefore, we hypothesize that Tfh cells and germinal center B cells differentially regulate germinal center activity by two distinct mechanisms. Here, we will ask how TSLPR signaling in each of these cell populations independently regulate the production of IgE/IgG1 antibodies in mouse models, and we will perform follow-up experiments to confirm that TLSP-blocking therapy can reduce the number of allergen-specific plasma cells and Tfh cells in patients with cat allergies. Overall, our research into the connection between TSLP receptor signaling and allergen-specific germinal center responses could build a foundation to establish novel therapeutics to treat or prevent the onset of allergic disease.

项目总结