Enhancing antigen-based therapy for T1D by T cell coreceptor tuning
通过 T 细胞辅助受体调节增强基于抗原的 T1D 治疗
基本信息
- 批准号:10593245
- 负责人:
- 金额:$ 23.33万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-11-11 至 2024-10-31
- 项目状态:已结题
- 来源:
- 关键词:AdjuvantAffectAntibodiesAntigensAutoantigensAutoimmune DiseasesAutoimmune ResponsesAutoimmunityB-Lymphocyte Differentiation AntigensB-LymphocytesBindingCD4 AntigensCD4 Positive T LymphocytesCD8B1 geneCellsClinicClinicalClinical ResearchCombination immunotherapyConceptionsDataDiabetes MellitusDiabetes preventionDisease ProgressionDoseDown-RegulationEquilibriumEragrostisEtiologyEventFOXO1A geneFOXP3 geneFrequenciesGenetic TranscriptionGoalsHumanImmune mediated destructionImmunotherapyInbred NOD MiceInsulinInsulin-Dependent Diabetes MellitusInterleukin-10MediatingModelingNaturePathogenicityPathologyPeptidesPreventionPropertyRegulatory T-LymphocyteSafetySelf AdministrationSelf ToleranceSignal TransductionT cell differentiationT-LymphocyteT-Lymphocyte SubsetsTestingTherapeuticTreatment EfficacyUp-RegulationVaccinationWorkacquired immunityadaptive immunitycombinatorialdiabetes mellitus therapydiabetogeniceffector T cellhumanized mouseimmune functionin vivoinsightmouse modelnovelnovel strategiespeptide vaccinationpre-clinicalpreventreceptortranscription factor
项目摘要
SUMMARY/ABSTRACT
Currently no cure exists for Type 1 diabetes (T1D). Due to immune-mediated destruction of the insulin-
producing cells, treatment of T1D is limited to daily exogenous insulin administration. Needed are
immunotherapies that effectively suppress cell autoimmunity longterm in order to prevent and treat T1D. One
approach is the administration of cell autoantigens to induce differentiation of adaptive regulatory CD4+ T
cells (aTreg). The approach is appealing since autoimmunity can be selectively targeted while leaving acquired
immunity unperturbed. A major hurdle, however, is inducing a sufficiently sized and subset diverse aTreg pool,
while avoiding expansion of pathogenic effector T cells (Teff). The size and nature of the aTreg pool is
particularly important at late preclinical T1D stages and at the onset of clinical diabetes, when a high frequency
of diabetogenic CD4+ and CD8+ Teff is found. This R21 outlines a novel approach to enhance the efficacy of
antigen therapy by “tuning” the function of CD4. CD4 binding to MHCII activates a signaling cascade that
contributes to overall TCR signaling strength. We hypothesize that modulating CD4 function and TCR signaling
strength, results in increased and selective induction of aTreg by antigen vaccination. In our model,
differentiation of aTreg subsets is determined by varying the level of coreceptor tuning (CoT). We will employ
nondepleting CD4 antibody to achieve CoT. Key objectives of this R21 are to gain initial insight into the
mechanism(s) by which CoT selectively promotes aTreg differentiation (Aim 1), and determine the therapeutic
efficacy of this combinatorial approach (Aim 2). If successful, combined CoT and self-antigen vaccination is
expected to be applicable not only for the prevention and treatment of T1D, but also for other T cell-mediated
autoimmune diseases and pathologies.
总结/摘要
目前还没有治愈1型糖尿病(T1 D)的方法。由于免疫介导的胰岛素破坏-
由于T1 D细胞产生,T1 D的治疗仅限于每天给予外源性胰岛素。需要的是
长期有效抑制T1 D细胞自身免疫的免疫疗法,以预防和治疗T1 D。一
一种方法是给予自体抗原,诱导适应性调节性CD 4 + T细胞分化,
细胞(aTreg)。这种方法很有吸引力,因为自身免疫可以选择性地靶向,同时使获得性
免疫力未受干扰。然而,一个主要的障碍是诱导足够大小和子集多样的aTreg库,
同时避免致病性效应T细胞(Teff)的扩增。aTreg池的大小和性质是
在晚期临床前T1 D阶段和临床糖尿病发作时,当高频率
糖尿病的CD 4+和CD 8 + Teff的发现。这R21概述了一种新的方法,以提高疗效,
通过“调节”CD 4的功能来进行抗原治疗。CD 4与MHCII结合激活信号级联,
有助于整体TCR信号强度。我们假设调节CD 4功能和TCR信号传导
强度,导致通过抗原疫苗接种增加的和选择性的aTreg诱导。在我们的模型中,
通过改变共受体调节(CoT)的水平来确定aTreg亚群的分化。我们会委聘
非消耗性CD 4抗体以实现CoT。R21的主要目标是初步了解
CoT选择性促进aTreg分化的机制(Aim 1),并确定治疗
这种组合方法的有效性(目的2)。如果成功,CoT和自身抗原联合疫苗接种是
预期不仅适用于T1 D的预防和治疗,而且适用于其他T细胞介导的疾病。
自身免疫性疾病和病理学。
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 }}
Roland M Tisch其他文献
Roland M Tisch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('Roland M Tisch', 18)}}的其他基金
ICES-based Pulsed Field Electromagnetic Field Therapy for Autoimmunity
基于 ICES 的自身免疫脉冲场电磁场治疗
- 批准号:
9903662 - 财政年份:2020
- 资助金额:
$ 23.33万 - 项目类别:
ICES-based Pulsed Field Electromagnetic Field Therapy for Autoimmunity
基于 ICES 的自身免疫脉冲场电磁场治疗
- 批准号:
10079462 - 财政年份:2020
- 资助金额:
$ 23.33万 - 项目类别:
Thymic and peripheral regulation of autoreactive T cells by coreceptor therapy
共受体治疗对胸腺和外周自身反应性 T 细胞的调节
- 批准号:
10395438 - 财政年份:2019
- 资助金额:
$ 23.33万 - 项目类别:
Thymic and peripheral regulation of autoreactive T cells by coreceptor therapy
共受体治疗对胸腺和外周自身反应性 T 细胞的调节
- 批准号:
10623181 - 财政年份:2019
- 资助金额:
$ 23.33万 - 项目类别:
The role of AIM2 in T cell-mediated autoimmunity
AIM2 在 T 细胞介导的自身免疫中的作用
- 批准号:
10321613 - 财政年份:2019
- 资助金额:
$ 23.33万 - 项目类别:
The role of AIM2 in T cell-mediated autoimmunity
AIM2 在 T 细胞介导的自身免疫中的作用
- 批准号:
10083178 - 财政年份:2019
- 资助金额:
$ 23.33万 - 项目类别:
Combinatorial beta Cell-Specific Cytokine Therapy to Reverse Type I Diabetes
逆转 I 型糖尿病的组合 β 细胞特异性细胞因子疗法
- 批准号:
8911506 - 财政年份:2015
- 资助金额:
$ 23.33万 - 项目类别:
Combinatorial Beta Cell-Specific Cytokine Therapy to Reverse Type I Diabetes
逆转 I 型糖尿病的β细胞特异性细胞因子组合疗法
- 批准号:
9240623 - 财政年份:2015
- 资助金额:
$ 23.33万 - 项目类别:
Islet-Specific Tolerance Induced by T Cell Co-Receptor Therapy in Type 1 Diabetes
T 细胞辅助受体治疗在 1 型糖尿病中诱导的胰岛特异性耐受
- 批准号:
8725412 - 财政年份:2014
- 资助金额:
$ 23.33万 - 项目类别:
Islet-Specific Tolerance Induced by T Cell Co-Receptor Therapy in Type 1 Diabetes
T 细胞辅助受体治疗在 1 型糖尿病中诱导的胰岛特异性耐受
- 批准号:
8829828 - 财政年份:2014
- 资助金额:
$ 23.33万 - 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:
$ 23.33万 - 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:
$ 23.33万 - 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:
$ 23.33万 - 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:
$ 23.33万 - 项目类别:
Fellowship
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:
$ 23.33万 - 项目类别:
Research Grant
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:
$ 23.33万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
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:
$ 23.33万 - 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:
$ 23.33万 - 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:
$ 23.33万 - 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:
$ 23.33万 - 项目类别:
Studentship