Regulatory B cell inhibition of immune responses to pathogens

调节性 B 细胞抑制病原体免疫反应

• 批准号: 8234178
• 负责人: THOMAS F TEDDER
• 金额: $ 32.39万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8234178
• 关键词: Acute; Adjuvant; Africa; Age; Alphavirus; Americas; Antibody Formation; Antigens; Arthralgia; Arthritis; Asia; Attenuated; Autoimmunity; B cell repertoire; B-Lymphocyte Subsets; B-Lymphocytes; Bacteria; Bioterrorism; CD4 Positive T Lymphocytes; CD8B1 gene; Capsid Proteins; Cell Count; Cell Survival; Cell physiology; Cells; Cellular Immunity; Cellular biology; Chikungunya virus; Disease; Drug Delivery Systems; Encephalitis; Encephalitis Viruses; Epidemic; Equilibrium; Equine Encephalomyelitis; Future; Goals; Human; Humoral Immunities; Immune response; Immunity; Immunization; In Vitro; Infection; Infectious Arthritis; Inflammatory; Inflammatory Response; Interleukin-10; Kinetics; Label; Laboratory mice; Lead; MS4A1 gene; Mediating; Modeling; Monoclonal Antibodies; Mouse Strains; Mus; Myositis; Pathogenesis; Pathology; Pharmaceutical Preparations; Play; Regulation; Research; Resources; Role; Signal Pathway; Signal Transduction; Source; Spleen; T cell response; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Transgenic Mice; Translations; Vaccination; Vaccine Therapy; Vaccines; Venezuela; Viral; Viral Antigens; Virus; Virus Diseases; base; biodefense; defined contribution; humanized monoclonal antibodies; immunopathology; in vivo; inhibitor/antagonist; pathogen; pre-clinical; preclinical study; receptor; response; small molecule; treatment strategy; vaccine development

B cells are the central source of long-term humoral immune responses to viral pathogens, but also serve critical regulatory functions during adaptive CD4+ T cell responses. It is unknown whether B cells contribute significantly to viral immune responses beyond antibody production or whether their manipulation can hasten or enhance immune responses. Important for emerging infections and biodefense, we have recently shown that B cells are essential for optimal CD4+ T cell priming during bacteria challenge. By contrast, monoclonal antibody (mAb)-induced B cell depletion augments Th1-type cellular immune responses in other models. This unexpected observation is explained by the identification of a potent regulatory B cell subset that dramatically attenuates Th1 immune responses and autoimmunity. We have labeled this phenotypically unique B cell subset that also secretes IL-10 as "B10" cells, which represent ~1% of total spleen B cells in young mice, and <1% of circulating human B cells. B10 cell numbers within tissues increase significantly in mice with autoimmunity and age. Thus, humoral and CD4+ T cell immune responses are balanced by both positive and negative B cell regulation. We have also identified a critical signaling pathway that is required For B10 cell survival in vivo. MAbs that inhibit this B cell-restricted survival signal induce rapid and semiselective B10 cell depletion in vivo, which has an adjuvant-like effect that enhances humoral antibody responses to T cell-dependent model antigens and Thl-type CD4+ T cell immune responses. Thus, B10 cells regulate both humoral and Th1 immune responses. We have also developed a humanized mAb to the same survival target and generated transgenic mice expressing the human survival receptor that will facilitate preclinical translation of these basic studies into human studies. The ability to manipulate B cell contributions to humoral and cell-mediated immunity by mAb treatment offers a new strategy for accelerating mmune responses during acute pathogen challenge. The focus of our proposed studies is to identify the extent that B cells and the B10 subset modulate humoral and cellular immune responses to alphaviruses, and to determine how B cells can be manipulated for therapeutic benefit and vaccine development.

B 细胞是针对病毒病原体的长期体液免疫反应的核心来源，但也可用于 适应性 CD4+ T 细胞反应期间的关键调节功能。目前尚不清楚 B 细胞是否有贡献 对抗体产生以外的病毒免疫反应有显着影响，或者它们的操作是否可以加速 或增强免疫反应。我们最近表明，对于新出现的感染和生物防御很重要 B 细胞对于细菌攻击期间最佳 CD4+ T 细胞启动至关重要。相比之下，单克隆 抗体 (mAb) 诱导的 B 细胞耗竭会增强其他模型中的 Th1 型细胞免疫反应。 这一意外的观察结果可以通过强效调节性 B 细胞亚群的鉴定来解释，该亚群 显着减弱 Th1 免疫反应和自身免疫。我们已经将此标记为表型 独特的 B 细胞亚群，也分泌 IL-10 作为“B10”细胞，约占脾 B 细胞总数的 1% 年轻小鼠，以及 <1% 的循环人类 B 细胞。组织内 B10 细胞数量显着增加 具有自身免疫和年龄的小鼠。因此，体液免疫反应和 CD4+ T 细胞免疫反应是通过两者来平衡的。 B 细胞的正向和负向调节。我们还确定了所需的关键信号通路 对于 B10 细胞在体内的存活。抑制这种 B 细胞限制性生存信号的单克隆抗体诱导快速和半选择性 体内 B10 细胞耗竭，具有增强体液抗体的佐剂样作用 对 T 细胞依赖性模型抗原的反应和 Thl 型 CD4+ T 细胞免疫反应。因此，B10 细胞调节体液和 Th1 免疫反应。我们还开发了一种人源化单克隆抗体 相同的生存目标并产生表达人类生存受体的转基因小鼠 促进这些基础研究的临床前转化为人类研究。操纵B细胞的能力 mAb 治疗对体液和细胞介导免疫的贡献提供了一种加速加速免疫的新策略 急性病原体攻击期间的免疫反应。我们提出的研究的重点是确定 B 细胞和 B10 亚群调节对甲病毒的体液和细胞免疫反应的程度， 并确定如何操纵 B 细胞以获得治疗效果和疫苗开发。