Therapeutic control of HSK by CD80
CD80 对 HSK 的治疗控制
基本信息
- 批准号:10534160
- 负责人:
- 金额:$ 41.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-01 至 2025-11-30
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAdverse effectsAffectAntibodiesApoptoticBackBindingBinding SitesBlindnessC57BL/6 MouseCD28 geneCD8-Positive T-LymphocytesCD80 geneCD8B1 geneCTLA4 geneCessation of lifeCicatrixCompensationCorneaDNADeveloped CountriesEyeEye InfectionsEye diseasesFailureFundingGangliaGenesGoalsHerpes stromal keratitisHerpesvirus 1Herpetic KeratitisImmuneImmune EvasionImmune responseImmune systemImmunizeIn VitroInbred BALB C MiceIndividualInfectionInflammatory ResponseKnockout MiceLightMapsMediatingMethodsMusMutatePathologyPhasePlayPredispositionPrimary InfectionProductionPublishingRecombinantsRecurrenceRecurrent diseaseRoleSimplexvirusStructure of trigeminal ganglionT cell responseT-LymphocyteTestingTherapeuticTimeTransgenic MiceTravelVaccinesViralViral Eye InfectionsViral Load resultVirionVirusVirus Replicationacute infectionclinically significantcorneal scardesignexhaustionimmune cell infiltrateimmune clearanceimmunogenicityin vivolatent infectionmouse modelneutralizing antibodynovelnovel strategiesoverexpressionpreventprogrammed cell death ligand 1programmed cell death protein 1promoterprophylacticreactivation from latencyrecombinant virusrecurrent infectionside effectvaccine trial
项目摘要
Project Summary
Following ocular primary herpes simplex virus type-1 (HSV-1) infection, the virus replicates in the eye
and establishes latency in the trigeminal ganglia (TG). In a latently infected individual, the virus can
occasionally reactivate and travel back to the eye causing recurrent disease. This reactivation from latency is
the major cause of corneal scarring (CS) in HSV-1 eye infections. We have shown previously that elicitation of
neutralizing antibody alone can protect immunized mice from eye disease and death; however, it does not
protect the immunized mice from virus replication in the eye and the establishment of latency in the TG. We
therefore focused on the mechanisms by which HSV-1 may subvert the ability of the immune system to clear
the virus, limit viral load, and prevent establishment of latency. We have shown that HSV-1 viral ICP22
suppresses the host CD80 co-stimulatory molecule and that this leads to reduced CD8+ CTL activity in the eye
and TG of ocularly infected mice, which in turn leads to less effective and delayed clearance of virus and
increased susceptibility to establishment of latency but at the same time protect host from HSV-1-induced
pathology. Our published and preliminary studies identified immune response regulatory mechanisms that
could be targeted to enhance the vaccine’s ability to reduce HSV-1 replication in the eye and prevent latency-
reactivation. By completing these studies, we expect to identify a novel approach to generating a vaccine with
both prophylactic and therapeutic applications that may control acute and latent infection without adverse
effects. This will be achieved by understanding how ICP22 and CD80 coordinately regulate virus replication in
the eye, eye disease, and latency-reactivation. Collectively, our Specific Aims focus on understanding
mechanisms of immune escape that protect the host from increased pathology while reducing viral clearance.
We propose to: (1) Determine whether blocking binding of ICP22 to the CD80 promoter will increase primary
HSV-1 infection, latency-reactivation, and eye disease in ocularly infected mice; and (2) Determine whether
exacerbation of CS by a recombinant HSV-1 expressing CD80 (HSV-CD80) or by viruses lacking the ICP22
suppressive effect is associated with the presence of PD-L1 but not CD28 or CTLA4.
CLINICAL SIGNIFICANCE: HSV-1 infections are among the most frequent serious viral eye infections in the
U.S. and are a major cause of viral-induced blindness. The results generated by this study will potentially
establish a previously undescribed mechanism underlying viral immune evasion that could be exploited to
better manage HSV infection. In light of recent failure of a large-scale phase III HSV-1 vaccine trials, our
approach may help design a more efficacious vaccine.
项目摘要
眼部原发性单纯疱疹病毒1型(HSV-1)感染后,病毒在眼部复制
并在三叉神经节(TG)中建立潜伏期。在潜伏感染的个体中,病毒可以
偶尔会重新激活并返回眼睛,导致复发性疾病。这种从延迟中的重新激活是
HSV-1眼感染中角膜瘢痕形成(CS)的主要原因。我们之前已经表明,
中和抗体单独可以保护免疫小鼠免于眼部疾病和死亡;然而,
保护免疫的小鼠免于在眼睛中病毒复制和在TG中潜伏期的建立。我们
因此,研究重点是HSV-1可能破坏免疫系统清除病毒的能力的机制。
病毒,限制病毒载量,并防止建立潜伏期。我们已经证明HSV-1病毒ICP 22
抑制宿主CD 80共刺激分子,这导致眼内CD 8 + CTL活性降低
和TG,这反过来又导致病毒清除效率降低和延迟,
增加对潜伏期建立的敏感性,但同时保护宿主免受HSV-1诱导的
病理我们已发表的和初步的研究确定了免疫应答调节机制,
可以靶向增强疫苗减少HSV-1在眼睛中复制和预防潜伏期的能力-
重新激活通过完成这些研究,我们希望确定一种新的方法来产生疫苗,
预防性和治疗性应用,可以控制急性和潜伏感染,而不会产生不良反应
方面的影响.这将通过了解ICP 22和CD 80如何协调调节病毒复制来实现。
眼睛、眼病和潜伏期再激活。总的来说,我们的具体目标侧重于理解
免疫逃逸机制,保护宿主免受病理增加,同时减少病毒清除。
我们建议:(1)确定阻断ICP 22与CD 80启动子的结合是否会增加原发性
HSV-1感染、潜伏期再激活和眼部感染小鼠的眼部疾病;和(2)确定是否
表达CD 80的重组HSV-1(HSV-CD 80)或缺乏ICP的病毒导致CS恶化22
抑制作用与PD-L1的存在有关,而与CD 28或CTLA 4无关。
临床意义:HSV-1感染是世界上最常见的严重病毒性眼部感染之一。
美国是病毒性失明的主要原因。这项研究产生的结果将有可能
建立了一种以前未描述的病毒免疫逃避机制,
更好地控制HSV感染。鉴于最近大规模III期HSV-1疫苗试验的失败,
这种方法可能有助于设计更有效的疫苗。
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 }}
HOMAYON GHIASI其他文献
HOMAYON GHIASI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('HOMAYON GHIASI', 18)}}的其他基金
Role of type 2 Innate Lymphoid Cells (ILC2s) in optic neuritis
2 型先天淋巴细胞 (ILC2) 在视神经炎中的作用
- 批准号:
10359644 - 财政年份:2021
- 资助金额:
$ 41.75万 - 项目类别:
Role of type 2 Innate Lymphoid Cells (ILC2s) in optic neuritis
2 型先天淋巴细胞 (ILC2) 在视神经炎中的作用
- 批准号:
10357860 - 财政年份:2019
- 资助金额:
$ 41.75万 - 项目类别:
Role of macrophages in control of ocular HSV
巨噬细胞在控制眼部 HSV 中的作用
- 批准号:
9144799 - 财政年份:2015
- 资助金额:
$ 41.75万 - 项目类别:
Role of macrophages in control of ocular HSV
巨噬细胞在控制眼部 HSV 中的作用
- 批准号:
9759926 - 财政年份:2015
- 资助金额:
$ 41.75万 - 项目类别:
Role of macrophages in control of ocular HSV
巨噬细胞在控制眼部 HSV 中的作用
- 批准号:
9330866 - 财政年份:2015
- 资助金额:
$ 41.75万 - 项目类别:
Role of macrophages in control of ocular HSV
巨噬细胞在控制眼部 HSV 中的作用
- 批准号:
10222691 - 财政年份:2015
- 资助金额:
$ 41.75万 - 项目类别:
相似海外基金
Unraveling Adverse Effects of Checkpoint Inhibitors Using iPSC-derived Cardiac Organoids
使用 iPSC 衍生的心脏类器官揭示检查点抑制剂的副作用
- 批准号:
10591918 - 财政年份:2023
- 资助金额:
$ 41.75万 - 项目类别:
Optimization of mRNA-LNP vaccine for attenuating adverse effects and analysis of mechanism behind adverse effects
mRNA-LNP疫苗减轻不良反应的优化及不良反应机制分析
- 批准号:
23K15383 - 财政年份:2023
- 资助金额:
$ 41.75万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Elucidation of adverse effects of combined exposure to low-dose chemicals in the living environment on allergic diseases and attempts to reduce allergy
阐明生活环境中低剂量化学品联合暴露对过敏性疾病的不良影响并尝试减少过敏
- 批准号:
23H03556 - 财政年份:2023
- 资助金额:
$ 41.75万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Green tea-based nano-enhancer as an adjuvant for amplified efficacy and reduced adverse effects in anti-angiogenic drug treatments
基于绿茶的纳米增强剂作为抗血管生成药物治疗中增强疗效并减少不良反应的佐剂
- 批准号:
23K17212 - 财政年份:2023
- 资助金额:
$ 41.75万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Effects of Tobacco Heating System on the male reproductive function and towards to the reduce of the adverse effects.
烟草加热系统对男性生殖功能的影响以及减少不利影响。
- 批准号:
22H03519 - 财政年份:2022
- 资助金额:
$ 41.75万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Mitigating the Adverse Effects of Ultrafines in Pressure Filtration of Oil Sands Tailings
减轻油砂尾矿压力过滤中超细粉的不利影响
- 批准号:
563657-2021 - 财政年份:2022
- 资助金额:
$ 41.75万 - 项目类别:
Alliance Grants
1/4-Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
1/4-破译ECT结果和不良反应的机制(DECODE)
- 批准号:
10521849 - 财政年份:2022
- 资助金额:
$ 41.75万 - 项目类别:
4/4-Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
4/4-破译ECT结果和不良反应的机制(DECODE)
- 批准号:
10671022 - 财政年份:2022
- 资助金额:
$ 41.75万 - 项目类别:
2/4 Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
2/4 ECT 结果和不良反应的破译机制(DECODE)
- 批准号:
10670918 - 财政年份:2022
- 资助金额:
$ 41.75万 - 项目类别:
Downsides of downhill: The adverse effects of head vibration associated with downhill mountain biking on visuomotor and cognitive function
速降的缺点:与速降山地自行车相关的头部振动对视觉运动和认知功能的不利影响
- 批准号:
2706416 - 财政年份:2022
- 资助金额:
$ 41.75万 - 项目类别:
Studentship