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

• 批准号: 10216948
• 负责人: Phillip P Domeier
• 金额: $ 6.86万
• 依托单位: BENAROYA RESEARCH INST AT VIRGINIA MASON
• 依托单位国家: 美国
• 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/10216948
• 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

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.

项目概要 全球高达 40% 的人口中检测到针对环境蛋白的 IgE 抗体，并且 在工业化国家，过敏性疾病的患病率持续上升。尽管有多种疗法可以缓解 抗体驱动的过敏反应或阻断抗体效应器功能，在没有治疗方法的情况下，高死亡率持续存在 治疗以及控制过敏原特异性抗体产生的机制仍然知之甚少。 我们小组和其他人之前的工作表明，胸腺基质淋巴细胞生成素（TSLP）是 过敏性疾病的发生，我们最近发现 TSLP 在控制过敏性疾病方面也发挥着额外的作用 IgE 和 IgG1 抗体在生发中心 (GC) 中产生。 GC B 细胞和滤泡辅助 T 细胞上调 当它们进入 GC 微环境时，表面 TSLP 受体 (TSLPR) 的表达，以及 TSLPR- 缺陷小鼠在免疫后产生的抗原特异性 IgG1 和 IgE 滴度显着降低。当CD4+ T 细胞特别缺乏 TSLPR 表达 (CD4creTSLPRF/F)，免疫小鼠产生相似频率的 T 细胞 抗原特异性生发中心，但产生 IgG1 且对抗原具有高亲和力的 B 细胞数量较少， 表明 T 细胞上的 TSLPR 表达可能是生发中心亲和力成熟所必需的。 因此，我们假设Tfh细胞和生发中心B细胞差异性地调节生发中心活性 通过两种不同的机制。在这里，我们将询问每个细胞群中的 TSLPR 信号如何 独立调控小鼠模型中IgE/IgG1抗体的产生，我们将进行后续跟进 实验证实 TLSP 阻断疗法可以减少过敏原特异性浆细胞的数量 对猫过敏的患者体内的 Tfh 细胞。总体而言，我们对 TSLP 受体信号传导之间联系的研究 过敏原特异性生发中心反应可以为建立新的治疗方法奠定基础 或预防过敏性疾病的发生。