Regulation of TSLP-Mediated Skin Inflammation
TSLP 介导的皮肤炎症的调节
基本信息
- 批准号:8061690
- 负责人:
- 金额:$ 39.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-05-01 至 2014-04-30
- 项目状态:已结题
- 来源:
- 关键词:AcuteAddressAllergic Contact DermatitisAllergic inflammationAntigensAreaAtopic DermatitisAutomobile DrivingCD4 Positive T LymphocytesCharacteristicsChronicCutaneousDendritic CellsDermalDevelopmentDiseaseEnvironmentEtiologyFamily history ofHealthIgEImmune responseInfiltrationInflammationInflammatoryInflammatory ResponseInterventionLeadMediatingMolecularMusMyeloid CellsPathogenesisPathway interactionsPemphigus VulgarisPopulationPruritusPsoriasisRegulationRoleSclerodermaSerumSkinSurfaceT-Cell DevelopmentT-LymphocyteTestingTh2 CellsTissuesTransgenic Organismsallergic responseatopycell motilitycytokineeosinophilhuman TSLP proteinimmunopathologyin vivokeratinocytelymph nodesmacrophagemast cellmicrobialmigrationnoveloverexpressionpathogenresearch studyresponseskin disorder
项目摘要
DESCRIPTION (provided by applicant): The skin is a barrier tissue with a large surface area in contact with the external environment and its own microbial flora. As such, immune responses in the skin must be tightly regulated to avoid unwanted and potentially harmful responses to innocuous environmental substances and commensal antigens, while allowing responses to a wide array of cutaneous pathogens. The consequences of dysregulated immune responses in the skin can be dire and include inflammatory diseases such as psoriasis, scleroderma and pemphigus vulgaris, as well as allergic responses that lead to acute and chronic atopic dermatitis (AD) and allergic contact dermatitis (ACD). We have shown that transgenic overexpression of the cytokine thymic stromal lymphopoietin (TSLP) specifically in the skin results in severe cutaneous inflammation resembling chronic AD. This inflammation is characterized by hyperactivation of CD4+ T cells and development of a strongly biased Th2 response, elevated serum levels of IgE, and severe dermal infiltration T cells, mast cells and eosinophils. Surprisingly, TSLP-overexpressing mice lacking T cells still develop the characteristic cutaneous inflammation, suggesting that myeloid cells are sufficient for the induction of TSLP-induced inflammation in the skin. The central hypotheses driving the experiments proposed in this study are that regulated expression of TSLP by keratinocytes activates resident myeloid cells in the skin, resulting in the induction of a cutaneous Th2 response and allergic inflammation in the skin. Strongly dysregulated TSLP expression in the skin causes myeloid cell hyperactivation, resulting in severe cutaneous immunopathology and development of strong Th2- mediated inflammation. To test these hypotheses and further define the role of TSLP in driving allergic inflammation, we will 1) Define the molecular pathways that lead to TSLP expression in the skin, 2) Determine the role of resident skin myeloid cells in initiating TSLP-mediated skin inflammation, and 3) Define the mechanisms by which TSLP controls dendritic cell migration during induction of TH2 responses in vivo. PUBLIC HEALTH RELEVANCE: Atopic dermatitis (AD) and allergic contact dermatitis (ACD) are common inflammatory disease of the skin that are characterized by intense pruritus and chronic eczematous plaques that are often associated with a personal or family history of atopy. The etiology and pathogenesis of these diseases remain poorly characterized. The proposed experiments will help define the role of a novel cytokine, TSLP, in the induction and progression of AD and ACD. This in turn will help guide efforts to develop new interventions for these and other skin inflammatory diseases that directly or indirectly target TSLP.
描述(由申请人提供):皮肤是一种屏障组织,表面积很大,与外部环境及其自身微生物菌群接触。因此,必须严格调节皮肤中的免疫反应,以避免对无害环境物质和共同抗原的不必要的和潜在的有害反应,同时允许对各种皮肤病的反应。皮肤中免疫反应失调的后果可能是可怕的,包括牛皮癣,硬皮病和pemphigus vulgaris等炎症性疾病,以及导致急性和慢性性感性皮肤炎(AD)和过敏性触及性触点性接触性触及性皮肤炎(ACD)的过敏反应(ACD)。我们已经表明,在皮肤中,细胞因子胸腺基质淋巴结蛋白(TSLP)的转基因过表达在皮肤上会导致类似于慢性AD的严重皮肤炎症。这种炎症的特征是CD4+ T细胞过度激活以及偏见的Th2反应,血清水平升高,精神真皮浸润T细胞,肥大细胞和嗜酸性粒细胞的升高。令人惊讶的是,缺乏TSLP表达TSLP的小鼠仍然会发展出特征性的皮肤炎症,这表明髓样细胞足以诱导TSLP诱导的皮肤炎症。这项研究中提出的实验的中心假设是,角质形成细胞调节TSLP的表达会激活皮肤中常驻的髓样细胞,从而导致皮肤皮肤TH2反应和过敏性炎症诱导。皮肤中TSLP表达强烈失调会导致髓样细胞过度激活,导致严重的皮肤免疫病理学和强烈TH2-介导的炎症的发展。 To test these hypotheses and further define the role of TSLP in driving allergic inflammation, we will 1) Define the molecular pathways that lead to TSLP expression in the skin, 2) Determine the role of resident skin myeloid cells in initiating TSLP-mediated skin inflammation, and 3) Define the mechanisms by which TSLP controls dendritic cell migration during induction of TH2 responses in vivo.公共卫生相关性:特应性皮炎(AD)和过敏性接触性皮炎(ACD)是皮肤的常见炎症性疾病,其特征在于瘙痒和慢性湿疹斑块,通常与特应特亚西的个人或家族史有关。这些疾病的病因和发病机理的特征仍然很差。提出的实验将有助于定义新型细胞因子TSLP在AD和ACD的诱导和进展中的作用。反过来,这将有助于指导为直接或间接针对TSLP的这些皮肤炎症性疾病开发新的干预措施。
项目成果
期刊论文数量(0)
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Daniel J Campbell其他文献
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- DOI:
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接受初次手术与放化疗治疗 T1-T2 口咽鳞状细胞癌的患者功能和生存结果的差异。
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10.1001/jamaoto.2023.1944 - 发表时间:
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Dev R Amin;R. Philips;Dylan G Bertoni;Eric V Mastrolonardo;Daniel J Campbell;A. Agarwal;Sruti Tekumalla;Zachary D Urdang;A. Luginbuhl;D. Cognetti;Joseph M. Curry - 通讯作者:
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Daniel J Campbell的其他文献
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{{ truncateString('Daniel J Campbell', 18)}}的其他基金
Reprogramming of tissue structural cells by cutaneous CD4+ T cells
皮肤 CD4 T 细胞对组织结构细胞的重编程
- 批准号:
10608777 - 财政年份:2023
- 资助金额:
$ 39.13万 - 项目类别:
Control of CD8+ T cell migration and activation by Flightless-1
Flightless-1 控制 CD8 T 细胞迁移和激活
- 批准号:
10155177 - 财政年份:2021
- 资助金额:
$ 39.13万 - 项目类别:
Mechanisms of autoimmune disease risk in IL2/IL2RA-dependent immune tolerance
IL2/IL2RA依赖性免疫耐受中自身免疫性疾病风险的机制
- 批准号:
10358624 - 财政年份:2021
- 资助金额:
$ 39.13万 - 项目类别:
Control of CD8+ T cell migration and activation by Flightless-1
Flightless-1 控制 CD8 T 细胞迁移和激活
- 批准号:
10366045 - 财政年份:2021
- 资助金额:
$ 39.13万 - 项目类别:
Mechanisms of autoimmune disease risk in IL2/IL2RA-dependent immune tolerance
IL2/IL2RA依赖性免疫耐受中自身免疫性疾病风险的机制
- 批准号:
10553203 - 财政年份:2021
- 资助金额:
$ 39.13万 - 项目类别:
Regulation of cutaneous immunity and tissue-repair by a specialized population of CD4+ T cells
特殊 CD4 T 细胞群对皮肤免疫和组织修复的调节
- 批准号:
9384627 - 财政年份:2017
- 资助金额:
$ 39.13万 - 项目类别:
Regulation of cutaneous immunity and tissue-repair by a specialized population of CD4+ T cells
特殊 CD4 T 细胞群对皮肤免疫和组织修复的调节
- 批准号:
9926223 - 财政年份:2017
- 资助金额:
$ 39.13万 - 项目类别:
Targeting the IL-2/regulatory T cell axis for autoimmune disease prevention in realistic animal models
靶向 IL-2/调节性 T 细胞轴在真实动物模型中预防自身免疫性疾病
- 批准号:
10307124 - 财政年份:2017
- 资助金额:
$ 39.13万 - 项目类别:
Targeting the IL-2/regulatory T cell axis for autoimmune disease prevention in realistic animal models
靶向 IL-2/调节性 T 细胞轴在真实动物模型中预防自身免疫性疾病
- 批准号:
10062808 - 财政年份:2017
- 资助金额:
$ 39.13万 - 项目类别:
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