Designer Tregs for restoring tolerance in patients with type 1 diabetes
用于恢复 1 型糖尿病患者耐受性的设计 Tregs
基本信息
- 批准号:9459191
- 负责人:
- 金额:$ 335.17万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-09-20 至 2021-08-31
- 项目状态:已结题
- 来源:
- 关键词:AffinityAlpha CellAnimal ModelAntigen TargetingAntigensAutoimmune DiabetesAutoimmune DiseasesAutoimmune ProcessAutoimmune ResponsesBeta CellBiological AvailabilityCD4 Positive T LymphocytesCell CommunicationCell TherapyCellsClinical TrialsDataDevelopmentDiabetes MellitusDiseaseDoseEngineeringEnsureEnvironmentExplosionFOXP3 geneFrequenciesFutureGoalsGrantHumanHuman EngineeringIL2RA geneImmuneImmune ToleranceImmune responseImmune systemImmunityImmunosuppressionImmunosuppressive AgentsIn VitroInflammationInflammatoryInfusion proceduresInsulin-Dependent Diabetes MellitusInterleukin 2 ReceptorInterleukin-2Islets of LangerhansKnowledgeMalignant NeoplasmsModalityModelingMusNatural Killer CellsNormal tissue morphologyPatientsPlayPopulationPreventionProcessProductionPropertyProtein EngineeringReactionRegulatory T-LymphocyteResearchRiskRoleSafetySelf-control as a personality traitSpecificityStructure of beta Cell of isletSuppressor-Effector T-LymphocytesSurface AntigensT-LymphocyteTestingTherapeuticTissuesUrsidae Familyautocrinebasecancer therapycellular engineeringchimeric antigen receptorclinical developmentcytokinedesigngenome wide association studyhumanized mouseimprovedin vivoisletmouse modelnext generationnovelpre-clinicalpreventprogramsreceptor expressionrepairedresponsesynthetic biologytissue repairtool
项目摘要
ABSTRACT
In type I diabetes, pancreatic islets are destroyed by an autoimmune reaction. Thus, a general strategic goal
for preventing islet loss is to locally suppress this autoimmune response, while avoiding systemic immune
suppression. FoxP3-expressing T regulatory cells (Tregs) are immune cells that play a central role in local
tolerance, and therefore could serve as a potential platform for a cell therapy to prevent islet loss. Tregs have
many attractive attributes as a suppressive cell therapy: they can exert dominant immunosuppressive actions,
through cell-cell interactions or production of suppressive cytokines; they can in principle be long lived; and
tolerance induced by Tregs can persist through infectious tolerance by conferring tolerogenic properties to
neighboring cells. In mouse models, single infusion of Tregs can prevent and reverse diabetes indefinitely.
The encouraging preliminary data in mouse models have let to the development of ongoing clinical trials of
Treg cell therapies in humans. Nonetheless, Treg cell therapy presents several key challenges: it is hard to
specifically target them to the islets and avoid systemic suppression, they are hard to expand in sufficient
numbers (especially relative to conventional effector T cells), and their cell fate can be changed, especially in
particular inflammatory microenvironments. In the past few years, however, there have been remarkable
advances in using conventional T cells for cancer therapy (e.g. CAR T cells), including an explosion of new
synthetic biology tools that can be used to precisely target T cells to disease tissues, to control their fate and
proliferation, and to even give them the capability to locally deliver non-natural therapeutic payloads. Here our
goal is to bring these new tools to bear on the problem of engineering improved islet-specific therapeutic
suppressive cells. Our aims are to:
1) engineer natural Tregs with improved targeting and recognition of islets
2) develop tools to selectively expand therapeutic Tregs in vivo and enhance their stability
3) design synthetic suppressor cells that disarm effectors, dampen inflammation and promote islet repair
These approaches wed cutting-edge synthetic biology with multiple strategies for developing therapeutic
suppressor cells. We will establish proof-of-concept data using mouse model of autoimmune diabetes and
apply them to test engineered human Tregs targeted to human islets using a humanized mouse model of
autoimmune islet inflammation. Successful completion of this study will provide preclinical data for future
implementation of these strategies in clinical trials.
摘要
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Next-generation regulatory T cell therapy.
- DOI:10.1038/s41573-019-0041-4
- 发表时间:2019-10
- 期刊:
- 影响因子:0
- 作者:Ferreira LMR;Muller YD;Bluestone JA;Tang Q
- 通讯作者:Tang Q
{{
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 }}
JEFFREY A BLUESTONE其他文献
JEFFREY A BLUESTONE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('JEFFREY A BLUESTONE', 18)}}的其他基金
Project 2 - Specificity and repertoire of Tregs in T1D
项目 2 - T1D 中 Tregs 的特异性和全部功能
- 批准号:
9151389 - 财政年份:2016
- 资助金额:
$ 335.17万 - 项目类别:
Donor-Alloantigen-Reactive Regulatory T Cell Therapy in Liver Transplantation
肝移植中供体同种异体抗原反应性调节性 T 细胞治疗
- 批准号:
8672260 - 财政年份:2014
- 资助金额:
$ 335.17万 - 项目类别:
Role of Innate Lymphoid Cells in Autoimmunity
先天淋巴细胞在自身免疫中的作用
- 批准号:
8637675 - 财政年份:2013
- 资助金额:
$ 335.17万 - 项目类别:
"Donor-Specific Regulatory T Cell Therapy in Liver Transplantation"
“肝移植中供体特异性调节性 T 细胞治疗”
- 批准号:
8728396 - 财政年份:2012
- 资助金额:
$ 335.17万 - 项目类别:
"Donor-Specific Regulatory T Cell Therapy in Liver Transplantation"
“肝移植中供体特异性调节性 T 细胞治疗”
- 批准号:
8264452 - 财政年份:2012
- 资助金额:
$ 335.17万 - 项目类别:
Spontaneous Autoimmune Model of Peripheral Neuropathy
周围神经病变的自发性自身免疫模型
- 批准号:
8116742 - 财政年份:2010
- 资助金额:
$ 335.17万 - 项目类别:
Genetically Engineered Antigen Specific Treg to Treat Autoimmunity
基因工程抗原特异性 Treg 治疗自身免疫性疾病
- 批准号:
7688822 - 财政年份:2009
- 资助金额:
$ 335.17万 - 项目类别:
相似海外基金
The Role of Arginine Transport on Pancreatic Alpha Cell Proliferation and Function
精氨酸转运对胰腺α细胞增殖和功能的作用
- 批准号:
10678248 - 财政年份:2023
- 资助金额:
$ 335.17万 - 项目类别:
Alpha cell-derived Extracellular Vesicles and Maternal Insulin Production
α细胞来源的细胞外囊泡和母体胰岛素的产生
- 批准号:
10681939 - 财政年份:2023
- 资助金额:
$ 335.17万 - 项目类别:
Targeting alpha-cell GPCRs to stimulate glucagon and counter hypoglycemia
靶向 α 细胞 GPCR 刺激胰高血糖素并对抗低血糖
- 批准号:
10427574 - 财政年份:2022
- 资助金额:
$ 335.17万 - 项目类别:
Arginine regulation of alpha cell proliferation and function
精氨酸调节α细胞增殖和功能
- 批准号:
10609909 - 财政年份:2022
- 资助金额:
$ 335.17万 - 项目类别:
Regulation of alpha-cell glucagon secretion by mitochondrial anaplerosis-cataplerosis
线粒体回补-回补对α细胞胰高血糖素分泌的调节
- 批准号:
10607392 - 财政年份:2022
- 资助金额:
$ 335.17万 - 项目类别:
Targeting alpha-cell GPCRs to stimulate glucagon and counter hypoglycemia
靶向 α 细胞 GPCR 刺激胰高血糖素并对抗低血糖
- 批准号:
10675646 - 财政年份:2022
- 资助金额:
$ 335.17万 - 项目类别:
Elucidating alpha cell defects in human type 1 diabetes using precision cut pancreas slice-on-a-chip coupled with high spatio-temporal microscopy
使用精密切割的胰腺切片结合高时空显微镜阐明人类 1 型糖尿病的 α 细胞缺陷
- 批准号:
457552 - 财政年份:2021
- 资助金额:
$ 335.17万 - 项目类别:
Studentship Programs
Defining alpha-cell proglucagon processing for type 2 diabetes treatment
定义 2 型糖尿病治疗的 α 细胞胰高血糖素原加工过程
- 批准号:
10331361 - 财政年份:2020
- 资助金额:
$ 335.17万 - 项目类别:
In vivo systems to discover mechanisms regulating human islet alpha cell function
体内系统发现调节人类胰岛α细胞功能的机制
- 批准号:
10623306 - 财政年份:2020
- 资助金额:
$ 335.17万 - 项目类别:
Defining alpha-cell PC1/3 expression regulation for type 2 diabetes
定义 2 型糖尿病的 α 细胞 PC1/3 表达调控
- 批准号:
10376866 - 财政年份:2020
- 资助金额:
$ 335.17万 - 项目类别: