Treatment of Primary Amoebic Meningoencephalitis via Modulation of Antibody Effector Functions
通过调节抗体效应器功能治疗原发性阿米巴脑膜脑炎
基本信息
- 批准号:10550175
- 负责人:
- 金额:$ 40.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-04-01 至 2026-01-31
- 项目状态:未结题
- 来源:
- 关键词:AcanthamoebaAmoeba genusAnimal ModelAntibodiesAntibody ResponseAntibody SpecificityAntibody-Dependent EnhancementAntibody-mediated protectionAntiparasitic AgentsBindingBiological AssayBrainCell surfaceCellsCentral Nervous SystemCentral Nervous System InfectionsCessation of lifeClinicalCoculture TechniquesComplementDataDiseaseEatingEffector CellEngineeringEpitopesEquilibriumFosteringGoalsGrowthHumanIgG1ImmuneImmune responseImmunityImmunoglobulin Class SwitchingImmunotherapeutic agentImmunotherapyIn VitroIndividualInfectionInterventionIntraventricularInvadedLaboratoriesLife ExpectancyLinkMediatingMembrane GlycoproteinsMeningoencephalitisMonoclonal AntibodiesMusNaegleriaNaegleria fowleriNervous System PhysiologyOutcomeParasitesParasitic DiseasesParasitic infectionPatientsPhenotypePopulationProliferatingRecombinantsSpecificitySurface AntigensTestingTherapeuticTherapeutic antibodiesTissuesTreatment EfficacyVaccinationVariantcell motilitycell typeclinically relevantcohorteffective therapyextracellularfunctional outcomesimmune activationimmunopathologyimproved outcomein vivointravital imagingmouse modelneuroprotectionneurotropicneutralizing antibodynovelnovel therapeutic interventionoptimal treatmentspassive antibodiespathogenpreservationpressurepreventprimary amebic meningoencephalitisprophylacticreceptorrestraint
项目摘要
Abstract:
Opportunistic CNS invasion by eukaryotic pathogens requires a highly coordinated, yet restrained, multi-
pronged immune response. CNS Infection by extracellular parasites such as Naegleria fowleri, Acanthamoeba,
and Balamuthia have proven nearly impossible to treat, yet immune directed therapies against N. fowleri have
the potential alter the course of almost universally fatal disease. The “brain eating amoeba” N. fowleri is
responsible for a devastating form of meningoencephalitis known as primary amoebic meningoencephalitis
(PAM) that is almost universally fatal (>97%) despite intensive clinical intervention, and new therapeutic
approaches are desperately needed. The protective relevance of Naegleria-reactive antibodies (Abs) in
humans is unclear, but animal models of PAM suggest that vaccinations and passive Ab administration
variably delay death and foster survival. Extracellular parasites cannot simply be neutralized by antibody, but
rather immunity relies on targeting antibody isotype specific effector mechanisms from immune cells. After
parasites are bound by antibody, isotype specific binding to fragment crystallizable receptors (FcRs) can direct
cell type specific effector functions against parasites. Prior studies of N. fowleri specific antibody responses
have not rigorously linked antibody specificity with the functional outcomes of individual\antibody isotypes,
creating a critical gap in understanding how antibody can optimally eliminate parasites from the within the
central nervous system (CNS) while not exacerbating immunopathology. We’ve generated a monoclonal Ab
specific for N. fowleri cell surface antigens that has shown strong anti-proliferative effects on parasites in vitro
and facilitates survival of infected hosts in vivo. This proposal seeks to define how combining anti-proliferative
effects of antibody and isotype specific binding can facilitate effective immune response against extracellular
CNS parasites while maintaining neuroprotection. Completion of this project will define new therapeutic
approaches to CNS infections that currently have few effective options and very poor outcomes.
摘要:
真核病原体侵入中枢神经系统需要一个高度协调,但受限制的,
免疫反应。CNS细胞外寄生虫感染,如福氏耐格里原虫、阿米巴原虫,
和Balamuthia已被证明几乎不可能治疗,但针对N.福勒里有
这种可能性改变了几乎普遍致命的疾病的进程。“食脑变形虫”N。福莱里群岛
导致了一种毁灭性的脑膜脑炎,称为原发性阿米巴脑膜脑炎
(PAM)尽管进行了密集的临床干预,
迫切需要采取各种办法。耐格里属反应性抗体(Abs)在
人类尚不清楚,但PAM的动物模型表明,接种疫苗和被动Ab给药
延缓死亡,促进生存。细胞外寄生虫不能简单地被抗体中和,
相反,免疫依赖于来自免疫细胞的靶向抗体同种型特异性效应器机制。后
寄生虫被抗体结合,同种型特异性结合片段可结晶受体(FcRs)可以指导
细胞类型特异性效应子功能对抗寄生虫。以往的研究N. Fowleri特异性抗体应答
没有严格地将抗体特异性与单个抗体同种型的功能结果联系起来,
在理解抗体如何最佳地从体内消除寄生虫方面造成了一个关键的差距。
中枢神经系统(CNS),而不加剧免疫病理学。我们制造了一种单克隆抗体
对N. Fowleri细胞表面抗原在体外对寄生虫显示出强的抗增殖作用
并促进受感染宿主在体内的存活。该提案旨在确定如何结合抗增殖
抗体和同种型特异性结合的作用可以促进针对细胞外
中枢神经系统寄生虫,同时保持神经保护。该项目的完成将定义新的治疗方法,
目前治疗CNS感染的有效方法很少,结果也很差。
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
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E. Ashley Moseman其他文献
E. Ashley Moseman的其他文献
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{{ truncateString('E. Ashley Moseman', 18)}}的其他基金
T cell/astrocyte fusions as a novel form of trained immunity to infection
T 细胞/星形胶质细胞融合作为一种新型的感染免疫训练形式
- 批准号:
10723089 - 财政年份:2023
- 资助金额:
$ 40.25万 - 项目类别:
Defining the molecular and anatomical basis of the blood-olfactory barrier (BOB)
定义血嗅屏障(BOB)的分子和解剖学基础
- 批准号:
10723087 - 财政年份:2023
- 资助金额:
$ 40.25万 - 项目类别:
Treatment of Primary Amoebic Meningoencephalitis via Modulation of Antibody Effector Functions
通过调节抗体效应器功能治疗原发性阿米巴脑膜脑炎
- 批准号:
10179955 - 财政年份:2021
- 资助金额:
$ 40.25万 - 项目类别:
Treatment of Primary Amoebic Meningoencephalitis via Modulation of Antibody Effector Functions
通过调节抗体效应器功能治疗原发性阿米巴脑膜脑炎
- 批准号:
10374907 - 财政年份:2021
- 资助金额:
$ 40.25万 - 项目类别:
Infectious Influence: Using fate mapping to determine the impact of viral infection sites on Alzheimer's disease initiation
感染影响:利用命运图谱确定病毒感染位点对阿尔茨海默病发病的影响
- 批准号:
10468164 - 财政年份:2021
- 资助金额:
$ 40.25万 - 项目类别:
Infectious Influence: Using fate mapping to determine the impact of viral infection sites on Alzheimer's disease initiation
感染影响:利用命运图谱确定病毒感染位点对阿尔茨海默病发病的影响
- 批准号:
10301193 - 财政年份:2021
- 资助金额:
$ 40.25万 - 项目类别: