Targeting tonsillar B cells for the induction of effective mucosal immunity to HIV
靶向扁桃体 B 细胞诱导针对 HIV 的有效粘膜免疫
基本信息
- 批准号:9390329
- 负责人:
- 金额:$ 77.52万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-07-12 至 2022-06-30
- 项目状态:已结题
- 来源:
- 关键词:AcuteAdjuvantAntibodiesAntibody FormationAntigen PresentationAntigensB-Lymphocyte SubsetsB-LymphocytesCCR9 geneCellsComplement ActivationDNADevelopmentDissectionDoseFlow CytometryGenetic TranscriptionHIVHIV InfectionsHIV envelope proteinHIV vaccineHIV-1HomingHumanHumoral ImmunitiesImmunizationImmunizeImmunoglobulin AImmunoglobulin GImmunoglobulin MImmunoglobulinsInfectionInjectableInterleukin-9IntestinesKineticsLymphoidMacaca mulattaMaintenanceMediatingMemoryMemory B-LymphocyteMicrobubblesMonitorMucosal ImmunityMucous MembraneNeedlesOral mucous membrane structurePalatine TonsilPhenotypePlasma CellsPopulationProcessProteinsResearchResolutionSIVSamplingSerologic testsSiteStimulusStructureStructure of germinal center of lymph nodeSystemTestingTonsilVaccinatedVaccinesVaginaVirusWorkbaseconditioningenv Gene Productsgp160insightintegrin alpha4beta7lymph nodesmucosal siteneutralizing antibodynovel strategiesnovel vaccinespathogenperipheral bloodplasmid DNApreventrectalresponsesimian human immunodeficiency virustraffickingtransmission processvaccine developmentvaccine response
项目摘要
Project Summary/Abstract
An effective HIV vaccine is likely to be dependent on sufficient quantity and quality of HIV Envelope (Env)-specific
antibody at the rectal and vaginal mucosa. Priming of the oral mucosa is viewed as a promising approach to generate
mucosal antibody at HIV entry sites, however the understanding of the mechanisms that mediate this process are
poorly understood. Our project seeks to precisely define the dynamics of inducing intestinal-mucosal plasma cells
through direct intra-tonsillar (i.t.) immunization, and empirically test strategies to tune this process for obtaining an
optimal mucosal antibody profile (localization, breadth, function, and durability) to achieve a protective HIV vaccine
strategy. A main emphasis for inducing HIV-specific B cell responses has been to evaluate adjuvants/stimuli that
target conventional B cell responses; leaving induction of non-conventional B cell responses, including those with
direct relevance to mucosal antibody production largely under-explored. IgM memory, one such unconventional B cell
population, is IgM memory, a major first line of defense against mucosal pathogens, and includes heterologous
subsets such as marginal zone and B-1 B cells, which are major precursors of mucosal IgA plasma cells. Our
research has demonstrated that IgM memory B cells are highly responsive to acute HIV infection and their
maintenance is highly correlated with Env-specific antibody development. Mechanisms to induce robust IgM
memory vaccine responses remain poorly defined, although our recent work has demonstrated the ability of IL-
9 and IL-33, known regulators of mucosal immunity, to promote the robust development of HIV Env-specific
IgM, in addition to increasing the breadth, magnitude, and durability of the Env-specific IgG and IgA response
when combined with the promising DNA/protein HIV Env immunogen platform VC10014 which elicits Tier 2
neutralizing antibody in rhesus macaques. Our central hypothesis is that conditioning the tonsil
microenvironment with IL-9 or IL-33 will enable the rapid induction of durable and effective mucosal humoral
immunity by the VC10014 HIV vaccine platform. This hypothesis will be tested by the following specific aims: 1)
Define the effect of the tonsil microenvironment on the induction of mucosal humoral immunity, 2) Evaluate the
protective ability of IL-9 or IL-33 adjuvanted VC10014 HIV vaccine platform, and 3) Identify strategies for
enhancing human tonsil primary B cell responses to immunization. This project will significantly advance our
insight into preventing HIV transmission and the mechanisms that control the development of protective
humoral mucosal responses to HIV.
项目摘要/摘要
一种有效的艾滋病毒疫苗很可能依赖于足够数量和质量的艾滋病毒包膜(Env)特异性
直肠和阴道粘膜有抗体。口腔粘膜的启动被认为是一种有希望的方法来产生
HIV进入部位的粘膜抗体,然而,对介导这一过程的机制的理解是
人们对此知之甚少。我们的项目试图精确地定义诱导肠粘膜浆细胞的动力学
通过直接扁桃体内(I.T.)免疫接种,并对调整这一过程的策略进行经验测试,以获得
实现保护性HIV疫苗的最佳黏膜抗体图谱(定位、广度、功能和持久性)
策略。诱导HIV特异性B细胞反应的一个主要重点是评估佐剂/刺激
靶向常规B细胞反应;留下非常规B细胞反应的诱导,包括那些
与粘膜抗体产生的直接相关性在很大程度上还没有得到充分的研究。免疫球蛋白记忆,一种这样的非常规B细胞
是免疫球蛋白M记忆,是抵御粘膜病原体的主要第一道防线,包括异源
如边缘区和B-1B细胞等亚群,它们是粘膜IgA浆细胞的主要前体。我们的
研究表明,IgM记忆B细胞对急性HIV感染高度敏感,它们的
维持与环境特异性抗体的产生高度相关。诱导强效IgM的机制
记忆疫苗的反应仍然没有明确的定义,尽管我们最近的工作已经证明了IL-
9和IL-33,已知的粘膜免疫调节剂,促进HIV Env特异性的强劲发展
免疫球蛋白除了增加环境特异性免疫球蛋白和免疫球蛋白A应答的广度、幅度和持久性外
当与前景看好的HIV Env免疫原平台VC10014结合时,VC10014会引发Tier 2
猕猴体内的中和抗体。我们的中心假设是调节扁桃体
使用IL-9或IL-33的微环境将能够快速诱导持久有效的粘膜体液
免疫力由VC10014 HIV疫苗平台提供。这一假设将通过以下具体目标进行检验:1)
确定扁桃体微环境在诱导粘膜体液免疫中的作用,2)评估
IL-9或IL-33佐剂VC10014 HIV疫苗平台的保护能力,以及3)确定策略
增强人类扁桃体初级B细胞对免疫的反应。这个项目将极大地推进我们的
对预防艾滋病毒传播的洞察和保护性发展的控制机制
对HIV的体液粘膜反应。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
James J Kobie其他文献
James J Kobie的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('James J Kobie', 18)}}的其他基金
The origin and future protective activity of SARS-CoV-2 RBD specific neutralizing antibodies
SARS-CoV-2 RBD 特异性中和抗体的起源和未来保护活性
- 批准号:
10390727 - 财政年份:2021
- 资助金额:
$ 77.52万 - 项目类别:
The origin and future protective activity of SARS-CoV-2 RBD specific neutralizing antibodies
SARS-CoV-2 RBD 特异性中和抗体的起源和未来保护活性
- 批准号:
10490907 - 财政年份:2021
- 资助金额:
$ 77.52万 - 项目类别:
Dynamics of the protective vaccine-induced human influenza neuraminidase B cell response
保护性疫苗诱导的人流感神经氨酸酶 B 细胞反应的动态
- 批准号:
10231081 - 财政年份:2019
- 资助金额:
$ 77.52万 - 项目类别:
Targeting tonsillar B cells for the induction of effective mucosal immunity to HIV
靶向扁桃体 B 细胞诱导针对 HIV 的有效粘膜免疫
- 批准号:
10186460 - 财政年份:2019
- 资助金额:
$ 77.52万 - 项目类别:
Dynamics of the protective vaccine-induced human influenza neuraminidase B cell response
保护性疫苗诱导的人流感神经氨酸酶 B 细胞反应的动态
- 批准号:
9765486 - 财政年份:2019
- 资助金额:
$ 77.52万 - 项目类别:
Dynamics of the protective vaccine-induced human influenza neuraminidase B cell response
保护性疫苗诱导的人流感神经氨酸酶 B 细胞反应的动态
- 批准号:
10468065 - 财政年份:2019
- 资助金额:
$ 77.52万 - 项目类别:
Dynamics of the protective vaccine-induced human influenza neuraminidase B cell response
保护性疫苗诱导的人流感神经氨酸酶 B 细胞反应的动态
- 批准号:
10018799 - 财政年份:2019
- 资助金额:
$ 77.52万 - 项目类别:
Targeting IgM Memory to Establish Protective B Cell Responses to HIV
靶向 IgM 记忆以建立针对 HIV 的保护性 B 细胞反应
- 批准号:
9020204 - 财政年份:2015
- 资助金额:
$ 77.52万 - 项目类别:
Targeting IgM Memory to Establish Protective B Cell Responses to HIV
靶向 IgM 记忆以建立针对 HIV 的保护性 B 细胞反应
- 批准号:
9222699 - 财政年份:2015
- 资助金额:
$ 77.52万 - 项目类别:
相似海外基金
Metachronous synergistic effects of preoperative viral therapy and postoperative adjuvant immunotherapy via long-term antitumor immunity
术前病毒治疗和术后辅助免疫治疗通过长期抗肿瘤免疫产生异时协同效应
- 批准号:
23K08213 - 财政年份:2023
- 资助金额:
$ 77.52万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Improving the therapeutic immunity of cancer vaccine with multi-adjuvant polymeric nanoparticles
多佐剂聚合物纳米粒子提高癌症疫苗的治疗免疫力
- 批准号:
2881726 - 财政年份:2023
- 资助金额:
$ 77.52万 - 项目类别:
Studentship
Evaluation of the Sensitivity to Endocrine Therapy (SET ER/PR) Assay to predict benefit from extended duration of adjuvant endocrine therapy in the NSABP B-42 trial
NSABP B-42 试验中内分泌治疗敏感性 (SET ER/PR) 测定的评估,用于预测延长辅助内分泌治疗持续时间的益处
- 批准号:
10722146 - 财政年份:2023
- 资助金额:
$ 77.52万 - 项目类别:
Countering sympathetic vasoconstriction during skeletal muscle exercise as an adjuvant therapy for DMD
骨骼肌运动期间对抗交感血管收缩作为 DMD 的辅助治疗
- 批准号:
10735090 - 财政年份:2023
- 资助金额:
$ 77.52万 - 项目类别:
AUGMENTING THE QUALITY AND DURATION OF THE IMMUNE RESPONSE WITH A NOVEL TLR2 AGONIST-ALUMINUM COMBINATION ADJUVANT
使用新型 TLR2 激动剂-铝组合佐剂增强免疫反应的质量和持续时间
- 批准号:
10933287 - 财政年份:2023
- 资助金额:
$ 77.52万 - 项目类别:
DEVELOPMENT OF SAS A SYNTHETIC AS01-LIKE ADJUVANT SYSTEM FOR INFLUENZA VACCINES
流感疫苗类 AS01 合成佐剂系统 SAS 的开发
- 批准号:
10935776 - 财政年份:2023
- 资助金额:
$ 77.52万 - 项目类别:
DEVELOPMENT OF SMALL-MOLECULE DUAL ADJUVANT SYSTEM FOR INFLUENZA VIRUS VACCINE
流感病毒疫苗小分子双佐剂体系的研制
- 批准号:
10935796 - 财政年份:2023
- 资助金额:
$ 77.52万 - 项目类别:
A GLYCOLIPID ADJUVANT 7DW8-5 FOR MALARIA VACCINES
用于疟疾疫苗的糖脂佐剂 7DW8-5
- 批准号:
10935775 - 财政年份:2023
- 资助金额:
$ 77.52万 - 项目类别:
Adjuvant strategies for universal and multiseasonal influenza vaccine candidates in the context of pre-existing immunity
在已有免疫力的情况下通用和多季节流感候选疫苗的辅助策略
- 批准号:
10649041 - 财政年份:2023
- 资助金额:
$ 77.52万 - 项目类别:
Adjuvant Photodynamic Therapy to Reduce Bacterial Bioburden in High-Energy Contaminated Open Fractures
辅助光动力疗法可减少高能污染开放性骨折中的细菌生物负载
- 批准号:
10735964 - 财政年份:2023
- 资助金额:
$ 77.52万 - 项目类别: