Enhancing Killer B Lymphocyte Function as a Treatment for Allergic Asthma

增强杀伤 B 淋巴细胞功能治疗过敏性哮喘

• 批准号: 8489559
• 负责人: STEVEN K. LUNDY
• 金额: $ 7.78万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-24 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8489559
• 关键词: Adoptive Transfer; Affect; Agammaglobulinaemia tyrosine kinase; Allergens; Antigens; Apoptosis; Asthma; Attention; Automobile Driving; B-Lymphocytes; Biological Assay; Biology; CD4 Positive T Lymphocytes; CD40 Ligand; Cell Death; Cell physiology; Cells; Cessation of life; Chronic; Data; Development; Disease; Drug Targeting; Extrinsic asthma; Gene Mutation; Goals; Helper-Inducer T-Lymphocyte; Human; Hypersensitivity; Immune; Immune response; Immunosuppression; In Vitro; Infection; Inflammatory; Interleukin-10; Interleukin-4; Interleukin-5; Intervention; JAK1 gene; JAK2 gene; Knockout Mice; Laboratories; Lung; Lymphocyte Function; Maintenance; Malignant Neoplasms; Manuscripts; Measures; Mediating; Methods; Modeling; Mouse Strains; Mus; NFAT Pathway; Pathogenesis; Pathology; Peptides; Pharmaceutical Preparations; Phenotype; Play; Population; Preparation; Principal Investigator; Production; Publishing; Receptor Signaling; Regulation; Relative (related person); Research; Role; STAT5A gene; STAT6 gene; Severities; Signal Pathway; Signal Transduction; Signaling Molecule; System; T-Lymphocyte; TNFRSF5 gene; Testing; Therapeutic Effect; Tissues; Transgenic Mice; Transgenic Model; Tumor Necrosis Factor Ligand Superfamily Member 6; airway inflammation; asthmatic patient; base; cytokine; eosinophil; experience; in vivo; inhibitor/antagonist; killings; mouse model; prevent; public health relevance; research study; response

DESCRIPTION (provided by applicant): Asthma is an inflammatory disease of the lower airways that is mediated by allergen-specific CD4+ T helper (TH) cells. In a mouse model of asthma, it was found that lung CD5+ B cells expressed the death-inducing molecule Fas ligand. These FasL+ 'killer' B cells were reduced in Xid mice which led to an increase in lung T cell cytokine production, and airway inflammation in response to chronic allergen challenge. These data suggested an important role for killer B cells in the regulation of asthma, and led to the current hypothesis that increasing killer B cell activity in the lung will suppress allergen-specifc TH cells and decrease airway inflammation and asthma. The following aims are proposed: Aim 1: Measure effects of adoptive transfer of killer/regulatory B cells on TH cell death and asthma pathogenesis. Aim 2: Investigate IL-5R signaling pathways involved in modulating FasL and IL-10 expression by B cells. The ability of a relatively small number of killer B cells in the lung to suppress asthma, makes it reasonable to suspect that increasing their numbers or potency even by a few fold will have a therapeutic effect. The regulatory functions of B cells are activated by IL-5, but the use of IL-5 as therapy for asthma is not advisable due to its proinflammatory effects on eosinophils. The long range goal of this research is to identify drug targets that selectively activate IL-5-dependent responses in B cells or other methods of inducing regulatory and/or killer B cell activity in asthmatic patients.

描述（由申请人提供）：哮喘是下部气道的炎症性疾病，是由过敏原特异性CD4+ T助手（Th）细胞介导的。在哮喘的小鼠模型中，发现肺CD5+ B细胞表达了诱导死亡的分子FAS配体。 XID小鼠中这些FASL+“杀伤” B细胞减少，从而导致肺T细胞细胞因子的产生增加，并响应慢性过敏原挑战而导致气道炎症。这些数据表明，杀手B细胞在调节哮喘中的重要作用，并导致当前的假设是，肺中杀伤B细胞的增加会抑制过敏原特异性TH细胞并减少气道炎症和哮喘。提出了以下目的：目标1：杀伤/调节B细胞对TH细胞死亡和哮喘发病机理的衡量效果。目标2：研究B细胞调节FASL和IL-10表达的IL-5R信号通路。肺中相对较少数量的杀手B细胞的能力 抑制哮喘，使怀疑即使有几倍甚至会产生治疗作用的人数或效力也是合理的。 B细胞的调节功能被IL-5激活，但由于其促炎作用而不建议使用IL-5作为哮喘治疗 在嗜酸性粒细胞上。这项研究的远距离目标是确定在B细胞中选择性激活IL-5依赖性反应的药物靶标或其他诱导哮喘患者中调节性和/或杀伤性B细胞活性的方法。