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Regulatory B cell inhibition of immune responses to pathogens

调节性 B 细胞抑制病原体免疫反应

基本信息

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
项目类别：
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

项目摘要

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细胞是对病毒病原体的长期体液免疫应答的中心来源，但也服务于在适应性CD 4 + T细胞应答中的关键调节功能。尚不清楚B细胞是否参与了除了抗体产生之外，病毒免疫反应的重要性，或者它们的操纵是否可以加速或增强免疫反应。我们最近发现， B细胞是细菌攻击期间最佳CD 4 + T细胞引发所必需的。相比之下，单克隆在其他模型中，单克隆抗体（mAb）诱导的B细胞耗竭增强了Th 1型细胞免疫应答。这种意想不到的观察结果可以通过鉴定一种有效的调节性B细胞亚群来解释，显著减弱Th 1免疫应答和自身免疫。我们将其标记为一种独特的B细胞亚群，也分泌IL-10作为“B10”细胞，其代表约1%的总脾B细胞，年轻小鼠和<1%的循环人B细胞。组织内B10细胞数量显著增加，小鼠自身免疫和年龄。因此，体液和CD 4 + T细胞免疫应答通过两者平衡。正向和负向B细胞调节。我们还确定了一个关键的信号通路，对于B10细胞在体内的存活。抑制这种B细胞限制的存活信号的单克隆抗体诱导快速和半选择性的体内B10细胞耗竭，其具有增强体液抗体的趋化剂样作用对T细胞依赖性模型抗原的免疫应答和Th 1型CD 4 + T细胞免疫应答。B10 细胞调节体液和Th 1免疫应答。我们还开发了一种人源化mAb，相同的生存目标和产生的转基因小鼠表达的人类生存受体，促进将这些基础研究转化为人类研究的临床前转化。操纵B细胞的能力单克隆抗体治疗对体液和细胞介导的免疫的贡献提供了一种新的策略，急性病原体攻击期间的免疫应答。我们建议的研究重点是确定在一定程度上，B细胞和B10亚群调节对甲病毒的体液和细胞免疫反应，并确定如何操纵B细胞以获得治疗益处和疫苗开发。