Modeling autoimmune pathogenesis and beta cell destruction by T1D immune systems
模拟 T1D 免疫系统的自身免疫发病机制和 β 细胞破坏
基本信息
- 批准号:10413178
- 负责人:
- 金额:$ 95.17万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-20 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAnimal ModelAntigensAutoantigensAutoimmuneAutoimmune DiseasesAutologousBeta CellCD8-Positive T-LymphocytesCell LineCellsComplexDevelopmentDiseaseEnvironmental ExposureFamily suidaeGenerationsGeneticGenetic EngineeringGenetic RiskGenotypeHLA-A2 AntigenHLA-DQ8 antigenHematopoietic stem cellsHeterogeneityHumanHybrid CellsHybridsIL2RA geneImmuneImmune systemImmunodeficient MouseImmunotherapyImplantIn VitroInbred MouseIndividualInsulinInsulin-Dependent Diabetes MellitusInterventionKnockout MiceLeadLuciferasesMediatingMethodologyMethodsMinisatellite RepeatsModelingMusPathogenesisPatientsPeptidesPopulationProtocols documentationRattusReporter GenesResearch DesignRoleSumSystemT-Cell DevelopmentT-Cell ReceptorT-LymphocyteTestingThymic TissueThymic epithelial cellThymus GlandTransgenic MiceTransgenic OrganismsVariantautoimmune pathogenesisautoreactive B cellautoreactive T cellautoreactivitycellular transductioncomorbiditydiabetes pathogenesisdiabetes riskdiphtheria toxin receptorepithelial stem cellfetalgenetic risk factorgenetic varianthuman diseasehuman fetal thymushuman modelhuman pluripotent stem cellhuman tissuehumanized mouseillness lengthimprovedin vivoisletislet allograftmouse modelnovelpatient populationpreventpromoterreceptor expressionreconstructionresponserisk variantscaffoldstem cellsthymocytethymus xenografttool
项目摘要
Project Summary
The study of Type 1 diabetes (T1D) pathogenesis has been limited by the insufficiency of animal models and
the heterogeneity of patient populations, who derive genetic risk from HLA and different assortments of about
60 non-HLA genetic variants. Given this complexity, there is a need for improved models of human T1D
pathogenesis involving diverse genetic backgrounds. We have developed humanized (HU) mouse models in
which T1D patient and healthy control (HC) immune systems are generated de novo from hematopoietic stem
cells (HSCs) in Personalized Immune (PI) mice and models introducing transgenic (Tg) autoreactive TCRs into
their HSCs and T cells. We have also developed methods of generating thymic epithelial cell (TEC) progenitors
and β cells from human pluripotent stem cells (hPSCs) that will increase our ability to test the influence of these
key cell populations on T1D risk. We will use these tools to address the hypothesis that HSC-intrinsic and
thymus-intrinsic genetic variants in T1D individuals lead to abnormal thymic selection of β cell antigen-
autoreactive TCRs. We will: Aim 1: Determine the impact of T1D-prone genotypes on selection of
autoreactive T cells in the human thymus. We have demonstrated negative selection of a Tg HLA-DQ8-
restricted insulin B9-23 peptide-specific TCR in HLA-DQ8+ thymi of HU mice. We will assess additional β cell-
autoreactive class I- and class II-restricted TCRs, determine the impact of both HSC and AIRE+ mTEC antigen
expression and compare selection of T1D patient vs HC thymocytes bearing β cell-reactive TCRs; Aim 2:
Determine the impact of T1D-prone genotypes of TECs on thymic selection of β cell-reactive T cells in
humanized mice. We will utilize a novel model in which hPSC-TECs create a “hybrid thymus” on a living scaffold
of fetal pig thymic tissue that supports human T cell development in HU mice. We will use this model with
genetically engineered hPSCs to determine the impact of human TEC expression of TID-associated genetic
variants on selection of autoreactive TCRs; Aim 3: Assess autoimmune interactions between hPSC-derived
β cells and autoreactive T cells in humanized mice. We have developed models for rejection of hPSC-derived
β cells in HU mice and for autoimmune β cell destruction by transducing autoreactive TCRs into their T cells. We
have generated a hPSC cell line that lacks all HLA except HLA-A2, evading rejection in HLA-A2+ immune
systems. These will be used in vivo and in vitro, with and without expression of an HLA Class II molecule, DQ8,
to model autoimmune destruction by TCR Tg T1D patient and HC-derived T cells, assessing the requirement for
Class II HLA and CD4 help for CD8 cell-mediated autoimmune β cell destruction. Our collaborative effort will
generate novel and robust systems to model human T1D, enhancing understanding of its pathogenesis and
providing a platform for testing of immunotherapies.
项目总结
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)
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Mark S Anderson其他文献
The sickness unto Deaf
致聋之病
- DOI:
10.1038/ni0909-934 - 发表时间:
2009-09-01 - 期刊:
- 影响因子:27.600
- 作者:
James M Gardner;Mark S Anderson - 通讯作者:
Mark S Anderson
Mark S Anderson的其他文献
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{{ truncateString('Mark S Anderson', 18)}}的其他基金
Project 2: STAT3 as a trigger for T1D
项目 2:STAT3 作为 T1D 的触发因素
- 批准号:
10576386 - 财政年份:2022
- 资助金额:
$ 95.17万 - 项目类别:
STAT3 variants as a rheostat of immune tolerance
STAT3 变体作为免疫耐受的变阻器
- 批准号:
10328097 - 财政年份:2022
- 资助金额:
$ 95.17万 - 项目类别:
Tuning peptide specifities for T cell tolerance in Type 1 diabetes
调整 1 型糖尿病 T 细胞耐受性的肽特异性
- 批准号:
10630946 - 财政年份:2022
- 资助金额:
$ 95.17万 - 项目类别:
Alterations of leukocyte integrin signaling leading to diabetes and autoimmunity
白细胞整合素信号的改变导致糖尿病和自身免疫
- 批准号:
10502136 - 财政年份:2022
- 资助金额:
$ 95.17万 - 项目类别:
Project 2: STAT3 as a trigger for T1D
项目 2:STAT3 作为 T1D 的触发因素
- 批准号:
10328102 - 财政年份:2022
- 资助金额:
$ 95.17万 - 项目类别:
Tuning peptide specifities for T cell tolerance in Type 1 diabetes
调整 1 型糖尿病 T 细胞耐受性的肽特异性
- 批准号:
10503923 - 财政年份:2022
- 资助金额:
$ 95.17万 - 项目类别:
Alterations of leukocyte integrin signaling leading to diabetes and autoimmunity
白细胞整合素信号的改变导致糖尿病和自身免疫
- 批准号:
10683384 - 财政年份:2022
- 资助金额:
$ 95.17万 - 项目类别:
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