The role of the innate immune system on Treg reprogramming in human autoimmune di
先天免疫系统在人类自身免疫性疾病中 Treg 重编程中的作用
基本信息
- 批准号:8495933
- 负责人:
- 金额:$ 73.41万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-07-01 至 2017-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAnatomyAntigensAutoimmune DiseasesAutoimmune ProcessAutoimmune ResponsesAutoimmunityBiochemical ProcessBiological AssayCD3 AntigensCXCR3 geneCandidate Disease GeneCell physiologyCell surfaceCellsCellular biologyCharacteristicsCollaborationsComplexDataDefectDevelopmentDiseaseEffectivenessEnvironmentEpigenetic ProcessExposure toFailureFrequenciesGeneticHealthHematological DiseaseHereditary DiseaseHomeostasisHumanIRF4 geneImmuneImmune ToleranceImmune responseImmune systemImmunityImmunosuppressive AgentsImmunotherapyIn VitroInbred NOD MiceIndividualInflammationInflammatoryInflammatory ResponseInsulin-Dependent Diabetes MellitusInterferon Type IIInterferonsInterleukin-1Interleukin-12Interleukin-17Interleukin-6LeadLigationLocationMediatingMolecularMultiple SclerosisMusPancreasPathogenesisPathway interactionsPatientsPeripheralPhenotypePhysiologicalPopulationPreventionProcessPropertyRegulatory T-LymphocyteRoleSTAT3 geneSignal TransductionSiteStagingSuppressor-Effector T-LymphocytesSurfaceT cell responseT-LymphocyteTherapeuticTherapeutic InterventionThymus GlandTissuesautoreactive T cellbasechemokine receptorcytokinedesigndiabeticin vivomigrationmouse modelnatalizumabnovelperipheral bloodperipheral tolerancepreventresponsetranscription factor
项目摘要
DESCRIPTION (provided by applicant): Multiple sclerosis (MS) and type 1 diabetes (T1D) are complex genetic diseases where pathogenic T cell autoimmune responses target and destroy self-tissue. However, the presence of T cells reactive to self alone is not sufficient for disease o occur as autoreactive T cells can be found in healthy control subjects; thus various means are available that control unwanted responses. One of the most important mechanisms is the activity of regulatory T cells (Tregs), which arise both in thymus and in the peripheral immune system as a consequence of exposure to antigens. While it was originally thought that Tregs represented a homogenous, end-stage differentiated population, recent data suggest that Tregs exist in immune response-specific subsets, which parallel the Th subsets that they control, can under certain conditions, be reprogrammed to secrete pro-inflammatory cytokines. Thus, Treg adaptation to the inflammatory milieu and chameleon-like propensity to take on Th-like phenotypes is physiologic and a fundamental attribute observed in mouse models. We have recently found that there is an increased frequency of Tregs from MS or T1D patients that secrete IFN-? compared to healthy controls, suggesting that this reprogramming may be present in humans as well and under certain conditions can be involved in the pathogenesis of autoimmune diseases. Thus, one fundamental question, addressed in this proposal is "to determine the mechanisms that generate Th-Tregs in autoimmune diseases and how these cells function in vivo under basal, inflammatory and therapeutic conditions." In addition, the induction and effectiveness of Treg responses are affected by their anatomic location. Factors that have central roles in Treg homeostasis such as TGF-¿, IL-6 and others, are expressed differently at mucosal surfaces, in the CNS, and in the pancreas, and may affect Treg differentiation locally. Thus, in this proposal we will address a second hypothesize that "the anatomic location and immune environment of Tregs dictates their pathway of differentiation in humans and that these processes are altered in individuals prone to autoimmunity." The following aims represent a concerted effort between two centers that will allow us to address these questions using the same experimental and disease platforms. 1. To determine what mechanisms are involved in the differentiation and stability of Th-like Treg subsets in healthy individuals and patients with MS and T1D. 2. To determine whether innate factors, driven by TLR ligation modulate Th-like Tregs. 3. To determine the function of human Th-like Tregs in vivo and the effects of immune therapies in humans and humanized mouse models. These studies will identify wide-ranging and disease-specific features of Th-Tregs in autoimmunity, and, hopefully, identify novel mechanisms that are important for prevention of MS, T1D, and potentially other autoimmune diseases. In addition, these studies may identify pathways that may be targeted by existing or novel immune therapeutics.
描述(由申请人提供):多发性硬化症 (MS) 和 1 型糖尿病 (T1D) 是复杂的遗传性疾病,其中致病性 T 细胞自身免疫反应瞄准并破坏自身组织。然而,仅对自身产生反应的 T 细胞的存在不足以导致疾病的发生,因为在健康对照受试者中也可以发现自身反应性 T 细胞;因此,有多种方法可以控制不需要的响应。最重要的机制之一是调节性 T 细胞 (Treg) 的活性,由于暴露于抗原,调节性 T 细胞 (Treg) 会在胸腺和外周免疫系统中产生。虽然最初认为 Tregs 代表同质的、终末期分化的群体,但最近的数据表明,Tregs 存在于免疫反应特异性亚群中,这些亚群与它们控制的 Th 亚群平行,在某些条件下可以被重新编程以分泌促炎细胞因子。因此,Treg 对炎症环境的适应和变色龙样倾向呈现 Th 样表型是生理学的,也是在小鼠模型中观察到的基本属性。我们最近发现 MS 或 T1D 患者分泌 IFN-α 的 Tregs 频率增加。与健康对照相比,这表明这种重编程也可能存在于人类中,并且在某些条件下可能参与自身免疫性疾病的发病机制。因此,本提案解决的一个基本问题是“确定在自身免疫性疾病中产生 Th-Treg 的机制以及这些细胞在基础、炎症和治疗条件下如何在体内发挥作用。”此外,Treg 反应的诱导和有效性受到其解剖位置的影响。在 Treg 稳态中起核心作用的因子,如 TGF-β、IL-6 等,在粘膜表面、中枢神经系统和胰腺中表达不同,并可能影响局部 Treg 分化。因此,在本提案中,我们将提出第二个假设,即“Tregs 的解剖位置和免疫环境决定了它们在人类中的分化途径,并且这些过程在易于发生自身免疫的个体中发生了改变。”以下目标代表了两个中心之间的共同努力,这将使我们能够使用相同的实验和疾病平台来解决这些问题。 1. 确定健康个体以及 MS 和 T1D 患者中 Th 样 Treg 亚群的分化和稳定性涉及哪些机制。 2. 确定 TLR 连接驱动的先天因素是否调节 Th 样 Tregs。 3. 确定人类Th样Treg的体内功能以及免疫疗法在人类和人源化小鼠模型中的效果。这些研究将确定 Th-Treg 在自身免疫中的广泛且特定于疾病的特征,并有望确定对于预防 MS、T1D 和潜在的其他自身免疫性疾病非常重要的新机制。此外,这些研究可能会确定现有或新型免疫疗法可能靶向的途径。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
David A. Hafler其他文献
Increased IL-12 production in progressive multiple sclerosis: Induction by activated CD4+ T cells via CD40 ligand
进行性多发性硬化症中 IL-12 的产生增加:通过 CD40 配体诱导活化的 CD4 T 细胞
- DOI:
10.1177/135245859600200519 - 发表时间:
1996 - 期刊:
- 影响因子:0
- 作者:
Howard L. Weiner;Konstantin E. Balashov;Derek R. Smith;Samia J. Khoury;David A. Hafler - 通讯作者:
David A. Hafler
Insulin auto-antigenicity in type 1 diabetes (Reply)
1 型糖尿病中的胰岛素自身抗原性(回复)
- DOI:
10.1038/nature04424 - 发表时间:
2005-11-23 - 期刊:
- 影响因子:48.500
- 作者:
David A. Hafler;Sally C. Kent;Yahua Chen;Lisa Bregoli;Sue M. Clemmings;Bernhard Hering;Norma Sue Kenyon;Camillo Ricordi - 通讯作者:
Camillo Ricordi
FOXP3+ regulatory T cells in the human immune system
人类免疫系统中的 FOXP3+调节性 T 细胞
- DOI:
10.1038/nri2785 - 发表时间:
2010-06-18 - 期刊:
- 影响因子:60.900
- 作者:
Shimon Sakaguchi;Makoto Miyara;Cristina M. Costantino;David A. Hafler - 通讯作者:
David A. Hafler
Antigen-driven peripheral immune tolerance. Suppression of organ-specific autoimmune diseases by oral administration of autoantigens.
抗原驱动的外周免疫耐受。
- DOI:
10.1007/978-3-642-51479-1_81 - 发表时间:
1991 - 期刊:
- 影响因子:5.2
- 作者:
Howard L. Weiner;Howard L. Weiner;Howard L. Weiner;Ariel Miller;Ariel Miller;Ariel Miller;Samia J. Khoury;Samia J. Khoury;Samia J. Khoury;Z. J. Zhang;Z. J. Zhang;Z. J. Zhang;Ahmad Al;Ahmad Al;Ahmad Al;Stanley A. Brod;Stanley A. Brod;Stanley A. Brod;Ofer Lider;Ofer Lider;Ofer Lider;Paul A. T. Higgins;Paul A. T. Higgins;Paul A. T. Higgins;Raymond A. Sobel;Raymond A. Sobel;Raymond A. Sobel;Makoto Matsui;Makoto Matsui;Makoto Matsui;Mohamed H. Sayegh;Mohamed H. Sayegh;Mohamed H. Sayegh;Charles C. J. Carpenter;Charles C. J. Carpenter;Charles C. J. Carpenter;George Eisenbarth;George Eisenbarth;George Eisenbarth;R. Nussenblatt;R. Nussenblatt;R. Nussenblatt;David A. Hafler;David A. Hafler;David A. Hafler - 通讯作者:
David A. Hafler
Functional Characterization of Autoreactive T-cells in Acute Disseminated Encephalomyelitis 199
急性播散性脑脊髓炎中自身反应性 T 细胞的功能特征 199
- DOI:
10.1203/00006450-199609000-00222 - 发表时间:
1996-09-01 - 期刊:
- 影响因子:3.100
- 作者:
Annette Pohi-Koppe;Sandra K. Burchett;David A. Hafler - 通讯作者:
David A. Hafler
David A. Hafler的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('David A. Hafler', 18)}}的其他基金
Targeting T cell dysfunction in glioblastoma: A proof-of-concept Phase 0/I trial of anti-TIGIT antibody AB154 in combination with anti-PD1 antibody AB122
靶向胶质母细胞瘤中的 T 细胞功能障碍:抗 TIGIT 抗体 AB154 与抗 PD1 抗体 AB122 联合的概念验证 0/I 期试验
- 批准号:
10346649 - 财政年份:2022
- 资助金额:
$ 73.41万 - 项目类别:
Targeting T cell dysfunction in glioblastoma: A proof-of-concept Phase 0/I trial of anti-TIGIT antibody AB154 in combination with anti-PD1 antibody AB122
靶向胶质母细胞瘤中的 T 细胞功能障碍:抗 TIGIT 抗体 AB154 与抗 PD1 抗体 AB122 联合的概念验证 0/I 期试验
- 批准号:
10573141 - 财政年份:2022
- 资助金额:
$ 73.41万 - 项目类别:
Systems Immune Profiling of Divergent Responses to Infection
对感染的不同反应的系统免疫分析
- 批准号:
10265709 - 财政年份:2020
- 资助金额:
$ 73.41万 - 项目类别:
Systems Immune Profiling of Divergent Responses to Infection
对感染的不同反应的系统免疫分析
- 批准号:
10205567 - 财政年份:2020
- 资助金额:
$ 73.41万 - 项目类别:
COVID-19 Supplement: Systems Immune Profiling of Divergent Responses to Infection
COVID-19 补充:对感染的不同反应的系统免疫分析
- 批准号:
10265708 - 财政年份:2020
- 资助金额:
$ 73.41万 - 项目类别:
Immunophenotyping for COVID-19 Cohort (IMPACC)
COVID-19 队列的免疫表型分析 (IMPACC)
- 批准号:
10265706 - 财政年份:2020
- 资助金额:
$ 73.41万 - 项目类别:
Yale Clinical Neuroscientist Training Program
耶鲁大学临床神经科学家培训计划
- 批准号:
10333938 - 财政年份:2012
- 资助金额:
$ 73.41万 - 项目类别:
Yale Clinical Neuroscientist Training Program
耶鲁大学临床神经科学家培训计划
- 批准号:
10210303 - 财政年份:2012
- 资助金额:
$ 73.41万 - 项目类别:
Yale Clinical Neuroscientist Training Program
耶鲁大学临床神经科学家培训计划
- 批准号:
8331031 - 财政年份:2012
- 资助金额:
$ 73.41万 - 项目类别:
相似海外基金
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 73.41万 - 项目类别:
Training Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 73.41万 - 项目类别:
Standard Grant
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 73.41万 - 项目类别:
Standard Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 73.41万 - 项目类别:
Fellowship
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 73.41万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 73.41万 - 项目类别:
Research Grant
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 73.41万 - 项目类别:
Studentship
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 73.41万 - 项目类别:
Operating Grants
New Tendencies of French Film Theory: Representation, Body, Affect
法国电影理论新动向:再现、身体、情感
- 批准号:
23K00129 - 财政年份:2023
- 资助金额:
$ 73.41万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
The Protruding Void: Mystical Affect in Samuel Beckett's Prose
突出的虚空:塞缪尔·贝克特散文中的神秘影响
- 批准号:
2883985 - 财政年份:2023
- 资助金额:
$ 73.41万 - 项目类别:
Studentship