B cells and humoral immunity in tuberculosis

结核病中的 B 细胞和体液免疫

• 批准号: 8584277
• 负责人: John R. Chan
• 金额: $ 70.36万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-15 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8584277
• 关键词: Acute; Adoptive Transfer; Affect; Animals; Antibodies; Antibody Formation; Antigen Presentation; Antigen-Antibody Complex; Antigen-Presenting Cells; Antitubercular Agents; Applications Grants; B-Lymphocytes; C57BL/6 Mouse; CD4 Positive T Lymphocytes; Cell Shape; Cell physiology; Cells; Cessation of life; Characteristics; Chronic; Collaborations; Data; Development; Drug resistance in tuberculosis; Epidemic; Exhibits; Extreme drug resistant tuberculosis; Goals; Granuloma; Granulomatous; HIV; Homing; Human; Humoral Immunities; Immune; Immune response; Immunity; Immunoglobulins; Infection; Inferior; Interleukin-10; Knock-out; Knowledge; Laboratories; Lead; Learning; Light; Lung; Lymphocyte; Lymphoid; Macaca; Measures; Mediating; Modeling; Mus; Mycobacterium tuberculosis; Neutrophil Infiltration; Nodule; Persons; Phenotype; Plasma; Play; Population; Predisposition; Prevention; Process; Production; Publications; Publishing; Regulation; Relative (related person); Reporting; Research; Resistance; Role; Serum; Signal Transduction; Structure of germinal center of lymph node; System; T cell response; T memory cell; T-Cell Development; T-Lymphocyte; Testing; Tissues; Transgenic Organisms; Tuberculosis; Tuberculosis Vaccines; Vaccination; Vaccines; Virulence; cost effective; cytokine; design; effective therapy; humoral immunity deficiency; infected B cell; memory CD4 T lymphocyte; mortality; mouse model; nonhuman primate; novel; pathogen; pulmonary granuloma; reactivation from latency; receptor; research study; response; treatment strategy; tuberculosis immunity; tuberculosis treatment; vaccination against tuberculosis; vaccine development; vaccine efficacy

DESCRIPTION (provided by applicant): The goal of this proposal is to characterize the mechanisms by which B cells contribute to the development of optimal anti-tuberculosis (TB) immunity. The importance of T cell immune response to Mycobacterium tuberculosis (Mtb) has been well established. The role of B cells in TB is not clearly defined. We and others have shown that B cells are a significant component of lung tuberculous granulomas in human and mice. They form conspicuous aggregates with features of germinal center B cells. Using the B cell-deficient mMT mouse, in conjunction with B cell transfer studies, we showed that B cells contribute significantly to anti-Mtb responses and are required for the optimal control of TB. Mice deficient in the inhibitory Fcg receptor IIB (FcgRIIB), relative to wildtype (WT) animals, exhibit an enhanced Th1 response in acute TB. The CD4+ T cells response of mMT mice is also altered in chronic infection. Together, these results provide strong evidence that B cells can regulate T cell immunity in TB, perhaps in part via FcgR engagement with antigen (Ag)-antibody (Ab) complex. We recently observed that BCG vaccination induces a Th1 response in mMT mice that is inferior to that observed in WT's. A recent study reports on the inability of BCG to optimally protect the CBA/xid mouse, another B cell-deficient strain. These BCG studies, together with published data that B cells can regulate T cell memory and secondary response to pathogen challenge, suggests that B cells contribute to vaccine efficacy. To stringently test the significance of B cells in regulating host immunity against Mtb, we initiated studies to examine the B cell response in a cynomolgus macaque (non-human primate; NHP) model, one that arguably most genuinely represents the human system. This study revealed that in the lungs of tuberculous NHP, as in human and mice, B cells can form discreet nodules and display enhanced expression of activation markers. We propose to use both murine and NHP TB models to rigorously test the hypotheses that: i) Specific functions of B cells contribute significantly to the host immune response to Mtb; ii) B cells are required for the development of effective T cell response in TB, including the CD4 T cell memory response; iii) B cells are essential for the development of optimal vaccine-engendered protection; and iv) Ag-Ab complex and FcgR can be exploited to enhance the host immune response to Mtb. We believe the proposed studies can shed light on the mechanisms by which B cells shape the host immune response to Mtb and lead to novel measures for harnessing humoral immunity to augment anti-TB immunity.

描述（由申请人提供）：本提案的目标是描述 B 细胞有助于形成最佳抗结核 (TB) 免疫力的机制。 T 细胞免疫反应对结核分枝杆菌 (Mtb) 的重要性已得到充分证实。 B 细胞在结核病中的作用尚不明确。我们和其他人已经证明，B 细胞是人和小鼠肺结核肉芽肿的重要组成部分。它们形成具有生发中心 B 细胞特征的明显聚集体。使用 B 细胞缺陷型 mMT 小鼠，结合 B 细胞转移研究，我们发现 B 细胞对抗 Mtb 反应有显着贡献，并且是最佳控制结核病所必需的。相对于野生型 (WT) 动物，抑制性 Fcg 受体 IIB (FcgRIIB) 缺陷的小鼠在急性结核病中表现出增强的 Th1 反应。 mMT 小鼠的 CD4+ T 细胞反应在慢性感染中也会发生改变。总之，这些结果提供了强有力的证据，证明 B 细胞可以调节结核病中的 T 细胞免疫，可能部分是通过 FcgR 与抗原 (Ag)-抗体 (Ab) 复合物的结合。我们最近观察到，BCG 疫苗接种在 mMT 小鼠中诱导的 Th1 反应低于在 WT 小鼠中观察到的反应。最近的一项研究报告称，BCG 无法最佳地保护 CBA/xid 小鼠（另一种 B 细胞缺陷品系）。这些 BCG 研究以及已发表的 B 细胞可以调节 T 细胞记忆和对病原体攻击的二次反应的数据表明，B 细胞有助于疫苗功效。为了严格测试 B 细胞在调节宿主针对 Mtb 的免疫方面的重要性，我们启动了研究，以检查食蟹猴（非人灵长类动物；NHP）模型中 B 细胞的反应，该模型可以说是最真实地代表人类系统的模型。这项研究表明，在结核性 NHP 的肺部（如人类和小鼠）中，B 细胞可以形成离散的结节，并表现出激活标记物表达的增强。我们建议使用小鼠和 NHP 结核病模型来严格检验以下假设： i) B 细胞的特定功能对宿主对 Mtb 的免疫反应有显着贡献； ii) B 细胞是结核病中形成有效 T 细胞反应所必需的，包括 CD4 T 细胞记忆反应； iii) B 细胞对于开发最佳疫苗产生的保护至关重要； iv) Ag-Ab 复合物和 FcgR 可用于增强宿主对 Mtb 的免疫反应。我们相信，拟议的研究可以揭示 B 细胞塑造宿主对 Mtb 的免疫反应的机制，并带来利用体液免疫增强抗结核免疫的新措施。