Induction of influenza virus-specific memory B cells

流感病毒特异性记忆 B 细胞的诱导

• 批准号: 6815545
• 负责人: MARK Y SANGSTER
• 金额: $ 24.77万
• 依托单位: UNIVERSITY OF TENNESSEE KNOXVILLE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6815545
• 关键词: B lymphocyte; Gammaherpesvirinae; antibody formation; drug administration routes; gene rearrangement; genetically modified animals; immunoglobulin A; immunoglobulin genes; immunologic memory; influenza vaccines; influenzavirus A; laboratory mouse; leukocyte activation /transformation; mucosal immunity; respiratory infections; secondary infection; vaccine evaluation

DESCRIPTION (provided by applicant): The emergence of novel strains of influenza A virus is an ever-present threat to human health worldwide. Currently, the cornerstone for the prevention of serious disease is intramuscular vaccination with inactivated influenza strains. The effectiveness of the vaccine is due to the induction of virus-specific serum antibodies (Abs), and also the generation of memory B cells (MBCs) that respond to "recall" antigen with rapid and vigorous Ab production. Despite the key role of MBCs in resistance to infection, quantitative aspects of MBC generation have received little attention. The major objective of the current proposal is a quantitative analysis of the MBC pool generated by influenza A virus infection of the respiratory tract, or by vaccination with inactivated virus. Studies will be undertaken using a mouse model system, and a limiting dilution assay that has been adapted for the determination of influenza-specific MBC frequencies. Aim 1 will focus on the frequency, anatomical distribution, and Ab isotype expression of MBCs induced by live virus infection. The hypothesis that mucosal infection generates a concentration of MBCs at mucosal surfaces will be tested. This work will be extended under Aim 2 to a characterization of the MBC pool induced by vaccination. The relationship between route of vaccine administration and MBC distribution and isotype expression will be investigated, and the effect of boosting regimens in "optimizing" the MBC pool will be examined. Systems established in Aims 1 and 2 will provide the basis for achieving Aim 3, in which the question of whether a heterologous virus infection can perturb a pre-existing, influenza-specific MBC pool will be addressed. The studies in this proposal will enhance our understanding of immunity to all viruses that target the respiratory tract, and will provide a basis for rational vaccine development. In addition, the systems established could be used in many other ways to address mechanistic questions related to the generation and maintenance of B cell memory.

描述（由申请人提供）：流感的新型菌株的出现是一种对全世界人类健康的威胁。目前，预防严重疾病的基石是肌内疫苗接种，流感毒株被灭活。疫苗的有效性是由于病毒特异性血清抗体（ABS）的诱导以及记忆B细胞（MBC）的产生，这些记忆B细胞（MBC）对“回忆”抗原具有快速而剧烈的AB产生。尽管MBC在抵抗感染中的关键作用，但MBC产生的定量方面很少受到关注。当前建议的主要目的是对由呼吸道的流感A病毒感染产生的MBC池进行定量分析，或通过灭活病毒疫苗接种。将使用小鼠模型系统进行研究，并为确定流感特异性MBC频率的限制稀释测定法。 AIM 1将重点放在活病毒感染引起的MBC的频率，解剖分布和AB同种型表达上。将测试粘膜感染在粘膜表面产生MBC浓度的假设。这项工作将在AIM 2下扩展到疫苗接种引起的MBC池的表征。将研究疫苗给药与MBC分布与同种型表达之间的关系，并将检查增强方案在“优化” MBC池中的影响。目标1和2中建立的系统将为实现目标3提供基础，在这个问题上，是否会解决异源病毒感染是否可以扰动现有的，流感特定的MBC池的问题。该提案中的研究将增强我们对针对呼吸道的所有病毒免疫的理解，并为理性疫苗开发提供基础。此外，建立的系统可以以许多其他方式使用，以解决与B细胞记忆的生成和维护有关的机械问题。