NAD and CD38: modulators of inflammation and immunity
NAD 和 CD38:炎症和免疫调节剂
基本信息
- 批准号:7699806
- 负责人:
- 金额:$ 25.72万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2007
- 资助国家:美国
- 起止时间:2007-06-01 至 2011-05-31
- 项目状态:已结题
- 来源:
- 关键词:AdjuvantAntigensB-LymphocytesBacterial InfectionsCD4 Positive T LymphocytesCell physiologyCellsCellular ImmunityClassCross-PrimingDataDendritic CellsDevelopmentEconomicsEnzymesGenerationsGoalsHealthHong KongHumanImmuneImmune responseImmunityInactivated VaccinesInfectionInflammationInflammatoryInfluenzaInfluenza A Virus, H5N1 SubtypeIntramuscularLeukocytesLigandsLymphoid TissueMaintenanceMeasuresMediatingMediator of activation proteinModelingMorbidity - disease rateMusNicotinamide adenine dinucleotideOrganOrganismPropertyProteinsProtocols documentationPublic HealthReceptor SignalingRecombinantsRespiratory physiologyRouteSafetySerotypingSignal TransductionSiteT-Cell ActivationT-LymphocyteTestingTissuesToll-like receptorsUnited StatesVaccinatedVaccinesVariantViralVirulentVirusVirus DiseasesWorkaluminum sulfatebasecell injurychemokine receptorenzyme activityextracellularimprovedinfluenza virus straininfluenza virus vaccineinfluenzavirusmigrationmortalitynovelnovel vaccinespandemic diseaseparticlepathogenreceptorresearch studyrespiratoryresponsesocialtrafficking
项目摘要
DESCRIPTION (provided by applicant): Influenza virus infections cause significant morbidity and mortality in the US and world. Since the current inactivated virus vaccines do not induce protective immunity to emerging strains of influenza virus, new vaccines are urgently needed. Unfortunately, the current inactivated virus vaccines do not contain adjuvant and do not induce lasting cellular immunity. Since the only adjuvant approved for use in humans is alum and alum enhances type 2 immune responses that are often detrimental for lung function, it is important to identify new, safe adjuvants that can be used in an influenza vaccine. Most commonly used experimental adjuvants are pathogen-derived and enhance immune responses by triggering Toll-like receptors (TLRs) which induce inflammation and tissue damage and activate dendritic cells. However, other molecules, unrelated to TLRs, also have the potential to modulate immune responses. One such molecule is the ecto-enzyme CD38 which catabolizes extracellular NAD, released by damaged and dying cells, to produce Ca2+mobilizing metabolites that modulate chemokine receptor signaling. CD38 and its substrate, NAD, are required for leukocyte migration and are also important for the generation of functional effector T cells. Interestingly, NAD, when co-administered with protein antigens and subthreshold amounts of adjuvant, significantly enhances T cell dependent immune responses. Based on these data, we hypothesize that NAD functions as a "co-adjuvant" to enhance innate and adaptive immune responses and that CD38 and extracellular NAD represent a novel class of immune modulators that are distinct from the TLRs. To test this hypothesis, we will first determine how NAD mediates its co-adjuvant properties (Aim 1). In Aim 2, we will determine how extracellular NAD regulates immune responses to influenza virus and in Aim 3, we will test the efficacy of a NAD-containing vaccine in enhancing immune protection to challenge infection with a new serotype of influenza virus. These experiments will facilitate the development of a new class of co-adjuvants that can be used safely in humans to improve cell-mediated immune protection to pathogenic intracellular organisms like influenza. Relevance to public health. Infections with influenza virus cause significant morbidity and mortality in the United States. In a typical year, approximately 100,000 peoples are hospitalized in the US due to influenza and 20,000-35,000 people die from the viral infection or secondary bacterial infections. Furthermore, the new emerging strains of influenza, such as the highly virulent H5N1 variant that appeared in Hong Kong in 1997, have the potential to trigger a worldwide pandemic with devastating social and economic consequences. Thus, it is one of NIAID's highest priorities (NOT-AI-05-013) that we develop more effective influenza vaccines that are protective against a wide array of different viral serotypes.
描述(由申请人提供):流感病毒感染在美国和世界范围内引起显著的发病率和死亡率。由于目前的灭活病毒疫苗不能对新出现的流感病毒株产生保护性免疫,因此迫切需要新的疫苗。不幸的是,目前的灭活病毒疫苗不含佐剂,也不能诱导持久的细胞免疫。由于唯一被批准用于人类的佐剂是明矾,而明矾可增强通常对肺功能有害的2型免疫反应,因此确定可用于流感疫苗的新型安全佐剂非常重要。最常用的实验性佐剂是病原体衍生的,通过触发toll样受体(tlr)来增强免疫反应,从而诱导炎症和组织损伤并激活树突状细胞。然而,与tlr无关的其他分子也有可能调节免疫反应。其中一个分子是外酶CD38,它分解细胞外NAD,由受损和死亡细胞释放,产生Ca2+动员代谢产物,调节趋化因子受体信号。CD38及其底物NAD是白细胞迁移所必需的,对功能性效应T细胞的产生也很重要。有趣的是,当NAD与蛋白抗原和亚阈值佐剂共同施用时,可显著增强T细胞依赖性免疫反应。基于这些数据,我们假设NAD作为一种“协同佐剂”来增强先天和适应性免疫反应,CD38和细胞外NAD代表了一类不同于tlr的新型免疫调节剂。为了验证这一假设,我们将首先确定NAD如何介导其共佐剂特性(目的1)。在aims 2中,我们将确定细胞外NAD如何调节对流感病毒的免疫反应;在aims 3中,我们将测试含有NAD的疫苗在增强免疫保护以对抗新血清型流感病毒感染方面的功效。这些实验将促进新一类辅助佐剂的开发,这些佐剂可安全地用于人类,以改善细胞介导的对流感等致病性细胞内生物的免疫保护。与公共卫生有关。在美国,流感病毒感染引起了显著的发病率和死亡率。在典型的一年里,美国约有10万人因流感住院,2万至3.5万人死于病毒感染或继发性细菌感染。此外,新出现的流感毒株,例如1997年在香港出现的高毒力H5N1变种,有可能引发全球大流行,造成毁灭性的社会和经济后果。因此,NIAID的最高优先事项之一(NOT-AI-05-013)是我们开发更有效的流感疫苗,以防止各种不同的病毒血清型。
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)
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Frances E. Lund其他文献
Transcription factor T-bet regulates the maintenance and differentiation potential of lymph node and lung effector memory B cell subsets
转录因子 T 细胞结合抑制因子调节淋巴结和肺效应记忆 B 细胞亚群的维持和分化潜能
- DOI:
10.1016/j.immuni.2025.05.021 - 发表时间:
2025-07-08 - 期刊:
- 影响因子:26.300
- 作者:
Christopher A. Risley;Michael D. Schultz;S. Rameeza Allie;Shanrun Liu;Jessica N. Peel;Anoma Nellore;Christopher F. Fucile;Christopher D. Scharer;Jeremy M. Boss;Troy D. Randall;Alexander F. Rosenberg;Frances E. Lund - 通讯作者:
Frances E. Lund
IgM Memory Cells: First Responders in Malaria
- DOI:
10.1016/j.immuni.2016.08.005 - 发表时间:
2016-08-16 - 期刊:
- 影响因子:
- 作者:
Sara L. Stone;Frances E. Lund - 通讯作者:
Frances E. Lund
This information is current as Infection in Mice Pneumocystis Clearance of T Cells for + Early Priming of CD 4 B Lymphocytes Are Required during the Feola
此信息是最新的,因为小鼠肺孢子虫感染在 Feola 期间需要清除 T 细胞以早期启动 CD 4 B 淋巴细胞
- DOI:
- 发表时间:
2015 - 期刊:
- 影响因子:0
- 作者:
M. Opata;M. Hollifield;Frances E. Lund;Troy D. Randall;Robert Dunn;B. Garvy;D. Feola - 通讯作者:
D. Feola
Signaling through CD38 augments B cell antigen receptor (BCR) responses and is dependent on BCR expression.
通过 CD38 的信号传导可增强 B 细胞抗原受体 (BCR) 反应,并且依赖于 BCR 表达。
- DOI:
10.4049/jimmunol.157.4.1455 - 发表时间:
1996 - 期刊:
- 影响因子:4.4
- 作者:
Frances E. Lund;N.;K. M. Kim;M. Reth;Maureen Howard - 通讯作者:
Maureen Howard
This information is current as MechanismsStrains of Influenza via Multiple B Cells Promote Resistance to Heterosubtypic and
该信息是最新的,因为机制流感菌株通过多个 B 细胞促进对异亚型和
- DOI:
- 发表时间:
2007 - 期刊:
- 影响因子:0
- 作者:
J. Rangel;D. Carragher;Ravi S. Misra;Kim L. Kusser;Louise Hartson;A. Moquin;Frances E. Lund;T. Randall - 通讯作者:
T. Randall
Frances E. Lund的其他文献
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{{ truncateString('Frances E. Lund', 18)}}的其他基金
TLR7 and TLR9-directed plasma cell formation: Dissecting the molecular basis for their differential dependence on IFN-induced signals
TLR7 和 TLR9 定向浆细胞形成:剖析它们对 IFN 诱导信号的差异依赖性的分子基础
- 批准号:
10642784 - 财政年份:2020
- 资助金额:
$ 25.72万 - 项目类别:
TLR7 and TLR9-directed plasma cell formation: Dissecting the molecular basis for their differential dependence on IFN-induced signals
TLR7 和 TLR9 定向浆细胞形成:剖析它们对 IFN 诱导信号的差异依赖性的分子基础
- 批准号:
10431929 - 财政年份:2020
- 资助金额:
$ 25.72万 - 项目类别:
Tissue and organ specific human B cell immunity
组织和器官特异性人类 B 细胞免疫
- 批准号:
10265689 - 财政年份:2020
- 资助金额:
$ 25.72万 - 项目类别:
TLR7 and TLR9-directed plasma cell formation: Dissecting the molecular basis for their differential dependence on IFN-induced signals
TLR7 和 TLR9 定向浆细胞形成:剖析它们对 IFN 诱导信号的差异依赖性的分子基础
- 批准号:
10032785 - 财政年份:2020
- 资助金额:
$ 25.72万 - 项目类别:
Identification and characterization of effector memory B cell populations that dominate memory responses to subsequent influenza infection and vaccination
效应记忆 B 细胞群的鉴定和表征,该细胞群主导对随后流感感染和疫苗接种的记忆反应
- 批准号:
10227903 - 财政年份:2020
- 资助金额:
$ 25.72万 - 项目类别:
TLR7 and TLR9-directed plasma cell formation: Dissecting the molecular basis for their differential dependence on IFN-induced signals
TLR7 和 TLR9 定向浆细胞形成:剖析它们对 IFN 诱导信号的差异依赖性的分子基础
- 批准号:
10214491 - 财政年份:2020
- 资助金额:
$ 25.72万 - 项目类别:
Identification and characterization of effector memory B cell populations that dominate memory responses to subsequent influenza infection and vaccination
效应记忆 B 细胞群的鉴定和表征,该细胞群主导对随后流感感染和疫苗接种的记忆反应
- 批准号:
10455632 - 财政年份:2020
- 资助金额:
$ 25.72万 - 项目类别:
Characterization of virus-specific human B cell subsets in lymphoid and non-lymphoid tissues
淋巴和非淋巴组织中病毒特异性人类 B 细胞亚群的表征
- 批准号:
10592418 - 财政年份:2019
- 资助金额:
$ 25.72万 - 项目类别:
Tissue and organ specific human B cell immunity
组织和器官特异性人类 B 细胞免疫
- 批准号:
10592408 - 财政年份:2019
- 资助金额:
$ 25.72万 - 项目类别:
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