Mast cell regulation of Th2 induction and tolerance breakdown in food allergy
肥大细胞对食物过敏中 Th2 诱导和耐受性破坏的调节
基本信息
- 批准号:10319164
- 负责人:
- 金额:$ 59.87万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-07-01 至 2025-11-30
- 项目状态:未结题
- 来源:
- 关键词:AdjuvantAffectAffinityAllergensAllergicAllergy to peanutsAnaphylaxisAnimalsAntibodiesAttenuatedB-LymphocytesBasophilsCell physiologyCellsChildDeveloped CountriesDevelopmentEndogenous FactorsEnterocytesEnvironmental Risk FactorEpithelial CellsEquilibriumFamilyFc ReceptorFoodFood HypersensitivityFosteringHealthIgEImmediate hypersensitivityImmuneImmune responseImmunityImmunoglobulin GImmunologicsImpairmentIngestionInterleukin-4IntestinesMediatingModelingMonoclonal AntibodiesMusPathogenicityPathway interactionsPatientsPlayPrevalenceProbabilityReactionRegulationRegulatory T-LymphocyteRoleSignal TransductionSpecificityT-LymphocyteTestingTh2 CellsVariantWorkallergic responsebasecytokineeffector T cellfood allergenfood protectionfunctional restorationgastrointestinal epitheliumhuman monoclonal antibodieshumanized mouseimmunoregulationin vivoinhibitormast cellmouse modeloral immunotherapypromoterprotective effectresponsesensortherapeutic targettranscriptomevillin
项目摘要
While food allergy has emerged as a major health issue, treatment options are quite limited. There is an
urgent need to identify the specific environmental and endogenous factors that prime and then sustain allergic
responses to foods so that new mechanism-based therapies can be developed. We have found that, IgE-
activated mast cells, best known for causing immediate hypersensitivity reactions including food anaphylaxis,
actually play a separate but critical role as food allergen sensors and adjuvants for Type 2 immune responses
and that the activating effects of food-specific IgE on mast cells can be countered by IgG antibodies of
corresponding specificity. Important questions remain unanswered, however: 1) What specific aspects of
Type 2 immunity (Th2, ILC2, IgE+ B cells) are enhanced by IgE-activated mast cells?, 2) Are these effects
mediated by mast cell cytokines?, 3) Is the protective effect of IgG antibodies in vivo, suppressing Th2 and
enhancing Treg responses, mediated by their negative signals, delivered via FcgR2b, specifically in mast cells
and can responses to food allergens be attenuated by using specific monoclonal IgG antibodies to activate this
suppressive pathway? These questions will be answered in this project under the following aims:
AIM 1: Establish how IgE-activated mast cells promote food allergy:
1.1 Test the impact of IgE-activated mast cells in vivo on emergence of Th2, Tfh and IgE+ B cells and
evaluate the contributions of mast cell derived Th2 cytokines
1.2 Examine mast cell effects on emerging effector RORgt+ vs. pathogenic GATA-3+, IRF-4+, IL-4+ Treg
1.3 Evaluate reciprocal TGFb-mediated inhibitory effects of Treg on mast cell functions
1.4 Examine the influence of IgE-activated mast cells on ILC2 induction in vivo: Roles of mast cell- vs. gut
epithelial cell-derived cytokines
AIM 2: Determine how IgG:FcgR2b signals can reset the immune response in food allergy:
2.1 Evaluate the direct role of IgG inhibitory signals in mast cells in suppression of Type 2 and restoration
of functional Treg responses in food allergy
2.2 Evaluate the effects of high-affinity human monoclonal peanut specific IgG antibodies (and their IgG
subclass swap variants) cloned from single B cells transcriptomes on IgE-mediated basophil activation
2.3 Use our humanized mouse model of peanut allergy to test the effects of monoclonal peanut-specific
IgE on immediate hypersensitivity responses (systemic anaphylaxis).
2.4 Test IgG effects on Th, Tfh and Treg responses in the humanized mice
虽然食物过敏已成为一个主要的健康问题,但治疗选择相当有限。有一个
迫切需要确定特定的环境和内源性因素,启动,然后维持过敏
从而可以开发新的基于机制的疗法。我们发现,IgE-
活化的肥大细胞,以引起包括食物过敏反应在内的速发型超敏反应而闻名,
作为食物过敏原传感器和2型免疫反应的佐剂,
食物特异性IgE对肥大细胞的激活作用可以被
相应的特异性。然而,重要的问题仍然没有答案:1)哪些具体方面
IgE激活的肥大细胞可增强2型免疫(Th 2、ILC 2、IgE+ B细胞),2)这些影响
由肥大细胞细胞因子介导?,3)IgG抗体在体内的保护作用,抑制Th 2和Th 3,
增强Treg应答,由其负信号介导,通过FcgR 2b递送,特别是在肥大细胞中
对食物过敏原的反应是否可以通过使用特异性单克隆IgG抗体来激活
抑制途径?本项目将根据以下目标回答这些问题:
目的1:确定IgE激活的肥大细胞如何促进食物过敏:
1.1检测IgE激活的肥大细胞在体内对Th 2、Tfh和IgE+ B细胞出现的影响,
评估肥大细胞衍生的Th 2细胞因子的贡献
1.2检查肥大细胞对新兴效应RORgt+ vs.致病性加塔-3+、IRF-4+、IL-4+ Treg的影响
1.3评价Treg对肥大细胞功能的相互TGF β介导的抑制作用
1.4检查IgE激活的肥大细胞对体内ILC 2诱导的影响:肥大细胞与肠道的作用
上皮细胞源性细胞因子
目的2:确定IgG:FcgR 2b信号如何重置食物过敏中的免疫应答:
2.1评估肥大细胞中IgG抑制信号在抑制2型和恢复中的直接作用
食物过敏中的功能性Treg反应
2.2评价高亲和力人单克隆花生特异性IgG抗体(及其IgG)的作用
从单个B细胞转录组克隆亚类交换变体)对IgE介导的嗜碱性粒细胞活化的影响
2.3使用我们的花生过敏的人源化小鼠模型来测试单克隆花生特异性
IgE对速发型超敏反应(全身性过敏反应)的影响。
2.4测试IgG对人源化小鼠中Th、Tfh和Treg应答的影响
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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Hans C Oettgen其他文献
The CC chemokine receptor 3 is essential for skin eosinophilia and for airway hyper-responsiveness to inhaled antigen in a murine model of allergic skin inflammation
- DOI:
10.1016/s0091-6749(02)81915-7 - 发表时间:
2002-01-01 - 期刊:
- 影响因子:
- 作者:
Weilie Ma;Paul J Bryce;Alison Humbles;Dhafer Laouini;Ali Yalcindag;Harri Tapio Alenius;Daniel Friend;Hans C Oettgen;Craig Gerard;Raif S Geha - 通讯作者:
Raif S Geha
The H<sub>1</sub> receptor antagonist, desloratadine, inhibits allergen-induced bronchial hyperreactivity and inflammation in a murine model of asthma
- DOI:
10.1016/s0091-6749(02)81146-0 - 发表时间:
2002-01-01 - 期刊:
- 影响因子:
- 作者:
Paul J Bryce;Raif S Geha;Hans C Oettgen - 通讯作者:
Hans C Oettgen
The complement receptor C3aR is an important regulator of Th cell polarization following epicutaneous sensitization with antigen
- DOI:
10.1016/s0091-6749(02)81988-1 - 发表时间:
2002-01-01 - 期刊:
- 影响因子:
- 作者:
Ali Yalcindag;Dhafer Laouini;Bao Lu;Paul J Bryce;Alison Humbles;Hans C Oettgen;Craig Gerard;Raif S Geha - 通讯作者:
Raif S Geha
Hans C Oettgen的其他文献
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{{ truncateString('Hans C Oettgen', 18)}}的其他基金
Mast cell regulation of Th2 induction and tolerance breakdown in food allergy
肥大细胞对食物过敏中 Th2 诱导和耐受性破坏的调节
- 批准号:
10531901 - 财政年份:2015
- 资助金额:
$ 59.87万 - 项目类别:
Mast cell regulation of Th2 induction and tolerance breakdown in food allergy
肥大细胞对食物过敏中 Th2 诱导和耐受性破坏的调节
- 批准号:
9197604 - 财政年份:2015
- 资助金额:
$ 59.87万 - 项目类别:
Role of IL-4R-alpha signaling in food allergen sensitization and anaphylaxis
IL-4R-α信号在食物过敏原致敏和过敏反应中的作用
- 批准号:
8484555 - 财政年份:2012
- 资助金额:
$ 59.87万 - 项目类别:
Role of IL-4R-alpha signaling in food allergen sensitization and anaphylaxis
IL-4R-α信号在食物过敏原致敏和过敏反应中的作用
- 批准号:
8044151 - 财政年份:2010
- 资助金额:
$ 59.87万 - 项目类别:
Role of IL-4R-alpha signaling in food allergen sensitization and anaphylaxis
IL-4R-α信号在食物过敏原致敏和过敏反应中的作用
- 批准号:
7869772 - 财政年份:2010
- 资助金额:
$ 59.87万 - 项目类别:
Regulation of Immune Responses by IgE and Mast Cells
IgE 和肥大细胞对免疫反应的调节
- 批准号:
7846424 - 财政年份:2009
- 资助金额:
$ 59.87万 - 项目类别:
Regulation of Immune Responses by IgE and Mast Cells
IgE 和肥大细胞对免疫反应的调节
- 批准号:
7030350 - 财政年份:2003
- 资助金额:
$ 59.87万 - 项目类别:
Regulation of Immune Responses by IgE and Mast Cells
IgE 和肥大细胞对免疫反应的调节
- 批准号:
6598688 - 财政年份:2003
- 资助金额:
$ 59.87万 - 项目类别:
Regulation of Immune Responses by IgE and Mast Cells
IgE 和肥大细胞对免疫反应的调节
- 批准号:
6703668 - 财政年份:2003
- 资助金额:
$ 59.87万 - 项目类别:
Regulation of Immune Responses by IgE and Mast Cells
IgE 和肥大细胞对免疫反应的调节
- 批准号:
7193514 - 财政年份:2003
- 资助金额:
$ 59.87万 - 项目类别:
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