IL-27 and downstream mechanisms in Alopecia Areata
斑秃中的 IL-27 及其下游机制
基本信息
- 批准号:10297577
- 负责人:
- 金额:$ 33.99万
- 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:2021-09-17 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:20 year oldAddressAdoptedAdoptive TransferAffectAlopecia AreataAnti-Inflammatory AgentsAntigen-Presenting CellsAntiinflammatory EffectAutoimmuneAutoimmune DiseasesAutoimmune ResponsesAutoimmunityAutomobile DrivingBlocking AntibodiesBone MarrowCD8-Positive T-LymphocytesCD8B1 geneCellsCellular biologyClinicalDataDependovirusDevelopmentDiseaseEndothelial CellsEpithelialEpithelial CellsEquilibriumFDA approvedFamiliarityFoundationsGene ExpressionGeneticGoalsHairHair follicle structureImmuneImmune TargetingImmune responseImmune systemInfiltrationInflammatoryInterleukin-10KnowledgeLeadLigandsLigationMHC Class I GenesMHC Class II GenesMaintenanceMediatingMedicalModelingMolecularMusOrganOutcomeParticipantPathogenesisPathogenicityPathway interactionsPatientsPharmaceutical PreparationsPhenotypePopulationProductionPropertyQuality of lifeRegulatory T-LymphocyteResearchRoleSignal PathwaySignal TransductionSiteSkinT cell differentiationT cell responseT-LymphocyteTherapeutic AgentsTherapeutic UsesTissuesUnited StatesUp-RegulationWorkautoimmune pathogenesisautoreactive T cellbasecell typecytokinedraining lymph nodeeffector T cellimmunoregulationimprovedin vivointerleukin-10 receptorlifetime riskmortalitymouse modelnew therapeutic targetnovel strategiesnovel therapeutic interventionoverexpressionpreservationpreventpsychosocialreceptorself esteemside effecttooltranscriptomicstumor
项目摘要
PROJECT SUMMARY
Alopecia areata (AA) is a common autoimmune disease in which the hair follicle is the target of attack
and results clinically in hair loss. Despite the associated high lifetime risk of approximately 2% and its substantive
psychosocial impact, no FDA approved treatments exist for AA. The lack of effective options for the population
that suffers from this disfiguring disease with significant psychosocial ramifications represents a significant unmet
medical need.
The absence of approved treatments is in part due to an incomplete understanding of the unbalanced
equilibrium between pathogenic immune responses and immunoregulatory mechanisms that prevent
autoimmunity in AA. Although many cytokines, pathways, and cell types have been hypothesized to prevent
immune attack of the hair follicle, it is unknown what factors participate in regulating autoimmune responses in
vivo. Identifying these critical immunoregulatory participants may not only deepen our understanding of AA
pathogenesis, but may reveal anti-inflammatory pathways that may be exploited to develop novel approaches to
treatment.
IL-27 is a cytokine with immunoregulatory properties that has been studied in various autoimmune,
infectious, and tumor models. The receptor for IL-27 is expressed by a wide array of immune cell types as well
as epithelial and endothelial cells, supporting its potential to modulate the immune system and critical cell
types that interact with the immune system. In particular, IL-27 has been shown to dampen conventional T cell
responses, increase the number of regulatory T cells, and induce naïve and previously activated CD4 and CD8
T cells to produce IL-10, a well-known cytokine with anti-inflammatory effects in most contexts. Our
preliminary data indicate that overexpression of IL-27 can substantially prevent the development of murine AA,
and further analysis revealed regulatory T cells and IL-10 as potential downstream candidates participating in
disease suppression.
We propose to study the mechanisms of AA suppression of exogenous IL-27 and its downstream
effects on regulating immune responses to the hair follicle and preventing the development of AA. We have
adopted and further developed a spontaneous AA mouse model to robustly develop disease in an inducible,
controlled, and well-characterized manner by adoptive transfer of activated pathogenic T cells. Combining our
AA model with newly developed genetic tools will allow us to dissect the mechanisms by which IL-27 may be
used to ablate AA pathogenesis and has the potential to reveal novel therapeutic strategies.
项目摘要
脱发Areata(AA)是一种常见的自身免疫性疾病,其中毛囊是攻击的目标
并在临床上导致脱发。尽管有大约2%的高终身风险和实质性风险
心理社会影响,没有FDA批准的AA治疗方法。缺乏有效的选择
这种毁容的疾病遭受了重大的社会心理后果,这是一个重要的未得到的疾病
医疗需求。
缺乏批准的治疗部分是由于对不平衡的不完整理解
致病性免疫复杂和免疫调节机制之间的平衡,以防止
AA的自身免疫性,尽管已经假设许多细胞因子,途径和细胞类型
毛囊的免疫攻击,尚不清楚哪些因素参与调节自身免疫反应
体内。确定这些关键的免疫调节参与者不仅可以加深我们对AA的理解
发病机理,但可能揭示了可以探索的抗炎途径,以开发出新的方法
治疗。
IL-27是一种具有免疫调节特性的细胞因子,已在各种自身免疫性中研究,
传染性和肿瘤模型。 IL-27的接收器也通过多种免疫细胞类型表达
作为上皮细胞和内皮细胞,支持其调节免疫系统和关键细胞的潜力
与免疫系统相互作用的类型。特别是,IL-27已显示为Damen常规T细胞
反应,增加调节性T细胞的数量,并影响幼稚和先前激活的CD4和CD8
T细胞产生IL-10,这是一种众所周知的细胞因子,在大多数情况下具有抗炎作用。我们的
初步数据表明,IL-27的过表达可以实质性地阻止鼠AA的发展,
进一步的分析揭示了调节性T细胞和IL-10作为参与的潜在下游候选者
疾病抑制。
我们建议研究AA抑制外源IL-27及其下游的机制
控制对毛囊的免疫反应并防止AA发育的影响。我们有
采用并进一步开发了一个赞助的AA小鼠模型,以在可诱导的,
通过自适应转移活化的致病性T细胞的自适应转移。结合我们
具有新开发的遗传工具的AA模型将使我们能够剖析IL-27可能是的机制
用于消融AA发病机理,并有可能揭示新的治疗策略。
项目成果
期刊论文数量(0)
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会议论文数量(0)
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Ali Jabbari其他文献
Ali Jabbari的其他文献
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{{ truncateString('Ali Jabbari', 18)}}的其他基金
IL-27 and downstream mechanisms in Alopecia Areata
斑秃中的 IL-27 及其下游机制
- 批准号:
10685308 - 财政年份:2021
- 资助金额:
$ 33.99万 - 项目类别:
IL-27 and downstream mechanisms in Alopecia Areata
IL-27 及其下游机制在斑秃中的作用
- 批准号:
10490304 - 财政年份:2021
- 资助金额:
$ 33.99万 - 项目类别:
Determining the role of T cell effector functions in Alopecia Areata
确定 T 细胞效应功能在斑秃中的作用
- 批准号:
10477192 - 财政年份:2020
- 资助金额:
$ 33.99万 - 项目类别:
Determining the role of T cell effector functions in Alopecia Areata
确定 T 细胞效应功能在斑秃中的作用
- 批准号:
10183173 - 财政年份:2020
- 资助金额:
$ 33.99万 - 项目类别:
Determining the role of T cell effector functions in Alopecia Areata
确定 T 细胞效应功能在斑秃中的作用
- 批准号:
10664944 - 财政年份:2020
- 资助金额:
$ 33.99万 - 项目类别:
Determining the role of T cell effector functions in Alopecia Areata
确定 T 细胞效应功能在斑秃中的作用
- 批准号:
10006640 - 财政年份:2020
- 资助金额:
$ 33.99万 - 项目类别:
Defining T helper cell associated cytokines and mechanisms in Alopecia Areata
斑秃中 T 辅助细胞相关细胞因子和机制的定义
- 批准号:
9979751 - 财政年份:2016
- 资助金额:
$ 33.99万 - 项目类别:
Defining T helper cell associated cytokines and mechanisms in Alopecia Areata
斑秃中 T 辅助细胞相关细胞因子和机制的定义
- 批准号:
9488636 - 财政年份:2016
- 资助金额:
$ 33.99万 - 项目类别:
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IL-27 and downstream mechanisms in Alopecia Areata
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