Engineering CAR Tregs for type 1 diabetes
工程 CAR Tregs 治疗 1 型糖尿病
基本信息
- 批准号:10354415
- 负责人:
- 金额:$ 19.28万
- 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:2021-09-24 至 2023-08-31
- 项目状态:已结题
- 来源:
- 关键词:Adoptive TransferAffectAnimal ModelAntibodiesAntibody AffinityAntigen TargetingAntigensAutoantigensAutoimmunityBeta CellCD8-Positive T-LymphocytesCell FractionCell Surface ProteinsCell SurvivalCell physiologyCell surfaceCellsClinical ResearchDiabetes MellitusDisease ProgressionEngineeringFundingGoalsGrantHumanHybridsImmuneImmune ToleranceImmune responseImmunosuppressionImmunotherapyIn VitroInbred NOD MiceInsulinInsulin-Dependent Diabetes MellitusIslets of Langerhans TransplantationLeadMediatingMethodsModelingMonoclonal AntibodiesMusPancreasPatientsPeptide/MHC ComplexPeptidesPre-Clinical ModelPreventionProteinsReagentRegulatory T-LymphocyteResearchRiskSafetySeriesSignal TransductionSpecificitySplenocyteT-Cell ReceptorT-LymphocyteTechnologyTestingTherapeuticTissuesTransgenic OrganismsTranslationsTreg therapyWorkantigen bindingautoreactivitychimeric antigen receptordiabeticdiabetogenicdraining lymph nodeexperimental studyextracellularhigh rewardhigh riskin vivoisletlymph nodesmodel developmentpreservationpreventrestorationsuccess
项目摘要
Summary
Type 1 diabetes (T1D) results from a breakdown in immunological tolerance and the resulting T cell-
mediated destruction of insulin producing beta cells in the pancreas. This is caused by defective
“regulatory” T cells (or Tregs), which normally suppress harmful immune responses. In T1D, Tregs stop
protecting beta cells. Work from T1D animal models has shown that therapeutic restoration of Tregs can
prevent disease progression, and clinical studies have shown the safety of this approach in humans.
Despite this initial success, there are significant hurdles for long term and global Treg therapy in T1D.
Current methods infuse large numbers of polyclonal Tregs that have not been selected for antigen
specificity, so they carry the risk of non-specific immunosuppression. Furthermore, it is difficult to expand
enough of these polyclonal Tregs required for therapy, and even then, only a small fraction of the cells
actually suppress autoimmunity. These challenges can be solved by creating “designer” Tregs that are
engineered for specificity and have the best chance of resetting immune tolerance. If successful, this
technology would lead to a more personalized and effective T1D immunotherapy. We recently developed
an approach to engineer antigen-specific Tregs by re-directing their specificity using chimeric antigen
receptors, or CARs. In this application, we will test if peptide specific MHC-CAR-Tregs prevent and/or
reverse T1D in NOD mice. We hypothesize that mouse Tregs expressing a hybrid insulin peptide-MHCII-
specific CAR will prevent T1D by restoring immune tolerance and suppressing autoreactive effector CD4+
and CD8+ T cell function to limit their accumulation in the pancreas.
总结
1型糖尿病(T1 D)是由免疫耐受性的破坏和由此产生的T细胞免疫缺陷引起的。
介导胰腺中产生胰岛素的β细胞的破坏。这是由缺陷造成的
“调节性”T细胞(或Tcells)通常抑制有害的免疫反应。在T1 D中,T1 D停止
保护β细胞T1 D动物模型的工作表明,Treg的治疗性恢复可以
预防疾病进展,临床研究表明这种方法在人类中是安全的。
尽管取得了初步成功,但T1 D患者的长期和整体Treg治疗仍存在重大障碍。
目前的方法输注大量的多克隆T细胞,这些T细胞尚未被选择用于抗原
特异性,因此它们具有非特异性免疫抑制的风险。再者,
治疗所需的足够多的这些多克隆T细胞,即使这样,也只有一小部分细胞
抑制自身免疫这些挑战可以通过创建“设计器”TUNK来解决,
设计的特异性,并有最好的机会重置免疫耐受。如果成功,这
这项技术将带来更个性化和更有效的T1 D免疫疗法。我们最近开发
通过使用嵌合抗原重定向其特异性来工程化抗原特异性TCLs的方法
受体或汽车。在本申请中,我们将测试肽特异性MHC-CAR-T细胞是否预防和/或抑制肿瘤的发生。
逆转NOD小鼠的T1 D。我们假设表达杂合胰岛素肽-MHCII-的小鼠T细胞
特异性CAR将通过恢复免疫耐受和抑制自身反应性效应物CD 4+来预防T1 D
和CD 8 + T细胞功能,以限制它们在胰腺中的积累。
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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Brian T Fife其他文献
Brian T Fife的其他文献
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{{ truncateString('Brian T Fife', 18)}}的其他基金
Identifying and preventing antigen specific T cells in diabetes
识别和预防糖尿病中的抗原特异性 T 细胞
- 批准号:
10436364 - 财政年份:2021
- 资助金额:
$ 19.28万 - 项目类别:
Identifying and preventing antigen specific T cells in diabetes
识别和预防糖尿病中的抗原特异性 T 细胞
- 批准号:
10634700 - 财政年份:2021
- 资助金额:
$ 19.28万 - 项目类别:
Identifying and preventing antigen specific T cells in diabetes
识别和预防糖尿病中的抗原特异性 T 细胞
- 批准号:
10296946 - 财政年份:2021
- 资助金额:
$ 19.28万 - 项目类别:
Engineering CAR Tregs for type 1 diabetes
工程 CAR Tregs 治疗 1 型糖尿病
- 批准号:
10495238 - 财政年份:2021
- 资助金额:
$ 19.28万 - 项目类别:
Multiplex immune analysis of antigen specific CD4+ T cells in autoimmune diabetes
自身免疫性糖尿病中抗原特异性 CD4 T 细胞的多重免疫分析
- 批准号:
9091431 - 财政年份:2015
- 资助金额:
$ 19.28万 - 项目类别:
Multiplex immune analysis of antigen specific CD4+ T cells in autoimmune diabetes
自身免疫性糖尿病中抗原特异性 CD4 T 细胞的多重免疫分析
- 批准号:
9271151 - 财政年份:2015
- 资助金额:
$ 19.28万 - 项目类别:
Multiplex immune analysis of antigen specific CD4+ T cells in autoimmune diabetes
自身免疫性糖尿病中抗原特异性 CD4 T 细胞的多重免疫分析
- 批准号:
8932879 - 财政年份:2015
- 资助金额:
$ 19.28万 - 项目类别:
Mechanisms of immune tolerance in autoimmune diabetes
自身免疫性糖尿病的免疫耐受机制
- 批准号:
8786472 - 财政年份:2013
- 资助金额:
$ 19.28万 - 项目类别:
Mechanisms of immune tolerance in autoimmune diabetes
自身免疫性糖尿病的免疫耐受机制
- 批准号:
8649238 - 财政年份:2013
- 资助金额:
$ 19.28万 - 项目类别:
Mechanisms of immune tolerance in autoimmune diabetes
自身免疫性糖尿病的免疫耐受机制
- 批准号:
9181377 - 财政年份:2013
- 资助金额:
$ 19.28万 - 项目类别:
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