Biologic Effects of Anti-Ganglioside Antibodies
抗神经节苷脂抗体的生物学效应
基本信息
- 批准号:8874311
- 负责人:
- 金额:$ 33.25万
- 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:2007-07-15 至 2019-04-30
- 项目状态:已结题
- 来源:
- 关键词:AcuteAffectAffinityAnimal ModelAnti-Inflammatory AgentsAnti-inflammatoryAntibodiesAntigen-Antibody ComplexAutoantibodiesAutoimmune ProcessAutoimmune ResponsesAxonBindingCD209 geneCell surfaceCell-Mediated CytolysisCellsComplexDataDependencyDevelopmentDiseaseFab ImmunoglobulinsFailureFc ImmunoglobulinsFc ReceptorFractionationFucoseGangliosidesGoalsGuillain-Barré SyndromeHealthHumanIgG ReceptorsImmuneImmune systemImmunoglobulin GImmunologic ReceptorsIn VitroIndividualInflammationInjuryIntravenous ImmunoglobulinsLectinLeftMass Spectrum AnalysisMediatingMediator of activation proteinMicrogliaMinorModelingMultiple SclerosisNatural regenerationNerveNerve CrushNeurogliaNeurologicNeuronsNeuropathyParalysedPathogenicityPathway interactionsPatientsPeripheral NervesPeripheral Nervous SystemPoliomyelitisPolysaccharidesPopulationPre-Clinical ModelRecombinantsRecoveryRecruitment ActivityResearchRoleSchwann CellsSeverity of illnessSialic AcidsSiteSpecificityStructureSurface Plasmon ResonanceSyndromeTestingTherapeuticTissuesTransgenic MiceTransplantationantibody-dependent cell cytotoxicityaxon regenerationbasecomparative efficacyglycosylationin vivoinhibiting antibodyinjuredmacrophagenerve injuryparent grantpreventreinnervationrepairedrole modelsialylation
项目摘要
DESCRIPTION (provided by applicant): After the near eradication of polio, Guillain-Barre syndrome (GBS) is the commonest cause of acute flaccid paralysis. Anti-ganglioside/glycan antibodies (Abs) are the most frequently recognized autoimmune responses in immune neuropathies grouped under the term GBS. Despite the availability of two immunomodulatory therapies, a significant proportion of patients are left with permanent neurologic sequelae. Patients with neurologic sequelae almost always have failure of axon regeneration and target reinnervation. Several studies indicate that specific anti-glycan Abs associate with poor recovery. Our group examined the effects of anti- glycan Abs on peripheral nerve repair and found these Abs inhibit regeneration of injured axons in preclinical models. The overall goals of this translational project are to study mechanisms underlying pathobiologic effects of anti-ganglioside Abs on axon regeneration and to develop strategies that could prevent the deleterious effects of anti-glycan Abs on nerve repair. Our preliminary results show that specific activating Fc-gamma receptors (Fc?Rs) particularly on macrophages recruited in the injured nerves are key determinants of Ab-mediated inhibition of nerve repair. Further, glycosylation of anti-ganglioside Abs is critical in their interactions with Fc?Rs and deglycosylation of anti-glyca Abs suppresses their inhibitory effects on nerve repair. Further, sialylated- fraction of human intravenous immunoglobulins (sIVIG), a minor component of IVIG, suppresses Ab-mediated inhibition of axon regeneration. We hypothesize that anti-glycan Abs bind to gangliosides on neural cell surfaces to form immune complexes on the proximal tips of injured axons and these in turn bind to specific activating Fc?Rs expressed by adjacent glial cells to induce tissue inflammation affecting axon regeneration. Furthermore, IgG Fc interactions with innate immune receptors are critically dependent on the IgG glycosylation and this glycosylation status can be manipulated (on pathogenic Abs and IVIG) to alter anti- ganglioside Ab- or IVIG-mediated effects. This renewal application will test these hypotheses by the following specific aims: Aim 1 will examine the role of specific Fc?Rs and glial cells expressing Fc?Rs in mediating nerve injury; Aim 2 will examine the role of N-glycan structures, carried by anti-glycan Abs, in their interactions with Fc?Rs to induce inflammation; and Aim 3 will examine the role of Fc/IgG sialylation as determinants of IVIG efficacy via the so-called 'DC-SIGN-Th2' anti-inflammatory pathway. These translational and 'proof of principle' studies have pathobiologic and therapeutic implications for failure of axon regeneration particularly that seen after immune insults/inflammation in autoimmune conditions like immune neuropathies and multiple sclerosis where failure of axonal repair is central to severity of the disease and recovery.
描述(由申请人提供):在几乎根除脊髓灰质炎之后,格林-巴利综合征(GBS)是急性弛缓性麻痹的最常见原因。抗神经节苷脂/聚糖抗体(Abs)是在GBS下的免疫神经病变中最常见的自身免疫反应。尽管有两种免疫调节疗法,但很大一部分患者留下了永久性的神经系统后遗症。神经系统后遗症患者几乎都有轴突再生和靶神经再生失败。一些研究表明,特异性抗聚糖抗体与恢复不良有关。本课组在临床前模型中检测了抗多糖抗体对周围神经修复的影响,发现这些抗体抑制损伤轴突的再生。本转化项目的总体目标是研究抗神经节苷脂抗体对轴突再生的病理作用机制,并制定预防抗多糖抗体对神经修复的有害作用的策略。我们的初步结果表明,特异性激活Fc- γ受体(Fc?Rs),特别是在受损神经中募集的巨噬细胞是抗体介导的神经修复抑制的关键决定因素。此外,抗神经节苷脂抗体的糖基化在它们与Fc?Rs和去糖基化抗糖抗体抑制其对神经修复的抑制作用。此外,人静脉注射免疫球蛋白(sIVIG)的唾液化部分(sIVIG的一个次要成分)抑制了抗体介导的轴突再生抑制。我们假设,抗聚糖Abs与神经细胞表面的神经节苷脂结合,在受损轴突近端形成免疫复合物,而这些复合物又与特异性激活的Fc?邻近胶质细胞表达的Rs诱导组织炎症,影响轴突再生。此外,IgG Fc与先天免疫受体的相互作用严重依赖于IgG的糖基化,这种糖基化状态可以被操纵(在致病性抗体和IVIG上),以改变抗神经节苷脂Ab或IVIG介导的作用。本更新申请将通过以下具体目标来测试这些假设:目的1将检查特定Fc?Rs和表达Fc?Rs介导神经损伤;目的2将研究由抗聚糖抗体携带的n -聚糖结构在它们与Fc?Rs诱导炎症;Aim 3将通过所谓的“DC-SIGN-Th2”抗炎途径研究Fc/IgG唾液化作为IVIG疗效决定因素的作用。这些转化和“原理证明”研究对轴突再生失败具有病理学和治疗意义,特别是在免疫损伤/自身免疫性疾病(如免疫神经病和多发性硬化症)炎症后,轴突修复失败是疾病严重程度和恢复的核心。
项目成果
期刊论文数量(0)
专著数量(0)
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KAZIM A SHEIKH其他文献
KAZIM A SHEIKH的其他文献
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{{ truncateString('KAZIM A SHEIKH', 18)}}的其他基金
Blockade of colony stimulating factor 1 receptor to reduce inflammatory nerve injury
阻断集落刺激因子 1 受体以减少炎症神经损伤
- 批准号:
10195632 - 财政年份:2021
- 资助金额:
$ 33.25万 - 项目类别:
Modulation of FcRn: A strategy to prevent autoantibody-mediated nerve injury
FcRn 的调节:预防自身抗体介导的神经损伤的策略
- 批准号:
8684787 - 财政年份:2014
- 资助金额:
$ 33.25万 - 项目类别:
Modulation of FcRn: A strategy to prevent autoantibody-mediated nerve injury
FcRn 的调节:预防自身抗体介导的神经损伤的策略
- 批准号:
8806622 - 财政年份:2014
- 资助金额:
$ 33.25万 - 项目类别:
Non-Invasive Imaging to Quantify Peripheral Nerve Injury and Repair in Clinic
无创成像在临床上量化周围神经损伤和修复
- 批准号:
8446439 - 财政年份:2011
- 资助金额:
$ 33.25万 - 项目类别:
Non-Invasive Imaging to Quantify Peripheral Nerve Injury and Repair in Clinic
无创成像在临床上量化周围神经损伤和修复
- 批准号:
8245788 - 财政年份:2011
- 资助金额:
$ 33.25万 - 项目类别:
Non-Invasive Imaging to Quantify Peripheral Nerve Injury and Repair in Clinic
无创成像在临床上量化周围神经损伤和修复
- 批准号:
8106764 - 财政年份:2011
- 资助金额:
$ 33.25万 - 项目类别:
Biologic Effects of Anti-Ganglioside Antibodies
抗神经节苷脂抗体的生物学效应
- 批准号:
8761854 - 财政年份:2007
- 资助金额:
$ 33.25万 - 项目类别:
Biologic effects of anti-ganglisiode antibodies
抗神经节苷脂抗体的生物学效应
- 批准号:
7695001 - 财政年份:2007
- 资助金额:
$ 33.25万 - 项目类别:
Biologic effects of anti-ganglisiode antibodies
抗神经节苷脂抗体的生物学效应
- 批准号:
7844987 - 财政年份:2007
- 资助金额:
$ 33.25万 - 项目类别:
Biologic effects of anti-ganglisiode antibodies
抗神经节苷脂抗体的生物学效应
- 批准号:
7320622 - 财政年份:2007
- 资助金额:
$ 33.25万 - 项目类别:
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