Chimeric antigen receptor (CAR) therapy for autoimmune arthritis
Chimeric antigen receptor (CAR) therapy for autoimmune arthritis
批准号:
9295586
负责人:
Edward F Rosloniec
金额:
$13.86万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-07-01 至 2019-06-30
关键词:
Adoptive TransferAdverse effectsAlpha CellAntigensArthritisAssesAutoantibodiesAutoimmune DiseasesAutoimmune ProcessAutoimmune ResponsesAutoimmunityB-LymphocytesBiological AssayCD28 geneCD3 AntigensCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCD8B1 geneComplementary DNAComplexDR1 geneDevelopmentDiseaseEngineeringEventFlow CytometryGenerationsGenetic EngineeringGoalsHLA-DR AntigensHLA-DR1 AntigenHLA-DRB1HistologyImmunizationImmunofluorescence ImmunologicLeadLinkLongevityLymphoidMHC Class II GenesMeasurementMeasuresMediatingMusOnset of illnessOrganPeptidesPhosphorylationPredispositionProductionRecombinantsRheumatoid ArthritisSeveritiesSignal TransductionSpecificityStaining methodStainsT-Cell ProliferationT-LymphocyteTNFRSF10A geneTestingTherapeuticTimeTransfectionVisualZAP-70 Geneautoimmune arthritisbasechimeric antigen receptorcytokineexperimental studygenetically modified cellshumanized mousein vivoinnovationkillingsmouse modelnovelperipheral bloodresponsetargeted treatment
中文摘要
摘要
英文摘要
Abstract
The focus of this proposal is the development of novel chimeric antigen receptor (CAR) T
cells that specifically target and eliminate CD4+ autoimmune T cells, and will therapeutically
alter the disease course of autoimmune arthritis. This innovative approach is based on the
generation of CD8+ T cells genetically engineered to express HLA-DR CAR molecules loaded
with an autoantigenic peptide. Using our well characterized HLA-DR humanized mouse model
of rheumatoid arthritis (RA), we will test the hypothesis that CD8+ T cells can be engineered to
express HLA-DR class II CAR with CD28/CD3ζ intracellular signaling domains, and that after
peptide loading of the CAR DR molecules on these CD8+ T cells, they will function as CTL and
specifically target and eliminate CD4+ autoimmune T cells. Two approaches will be pursued to
generate antigen specific targeting of the CD4+ T cells. Initial experiments will be focused on
using DRB1 cDNA encoding an antigenic peptide that is covalently linked to the DR1 molecule.
This approach will be used to demonstrate the feasibility of the CAR CTL generation and their
function in vivo in the inhibition of an active autoimmune disease. In the second approach, we
will generate CAR CTL with “empty “ DR1 molecules, and soluble peptide will be used to load
the DR1 CAR before measuring the CAR CTL function. This approach will allow for targeting
CD4+ T cells specific for posttranslationally modified (PTM) peptides which are components of
the autoimmunity of the mouse model and potentially important components of RA
autoimmunity. Through the specific aims of this proposal, we will investigate the specificity of
the CAR T cells, their ability to receive signals through the CAR CD28/CD3 domains, and their
efficacy in treating an active autoimmune disease.
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会议论文
Structure-function of HLA-DR, peptides, and T cells in autoimmune arthritis
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批准号:8305422
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项目类别:
-
资助金额:$0.0万
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财政年份:2010
-
负责人:Edward F Rosloniec
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依托单位:
Structure-function of HLA-DR, peptides, and T cells in autoimmune arthritis
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批准号:8391633
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项目类别:
-
资助金额:$0.0万
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财政年份:2010
-
负责人:Edward F Rosloniec
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依托单位:
Structure-function of HLA-DR, peptides, and T cells in autoimmune arthritis
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批准号:8597409
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项目类别:
-
资助金额:$0.0万
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财政年份:2010
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负责人:Edward F Rosloniec
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依托单位:
Structure-function of HLA-DR, peptides, and T cells in autoimmune arthritis
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批准号:8046605
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项目类别:
-
资助金额:$0.0万
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财政年份:2010
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负责人:Edward F Rosloniec
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依托单位:
MECHANISMS OF AUTOIMMUNE ARTHRITIS
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批准号:2593298
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项目类别:
-
资助金额:$17.5万
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财政年份:1998
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负责人:Edward F Rosloniec
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依托单位:
MECHANISMS OF AUTOIMMUNE ARTHRITIS
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批准号:6375096
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项目类别:
-
资助金额:$19.11万
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财政年份:1998
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负责人:Edward F Rosloniec
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依托单位:
MECHANISMS OF AUTOIMMUNE ARTHRITIS
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批准号:2899929
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项目类别:
-
资助金额:$18.02万
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财政年份:1998
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负责人:Edward F Rosloniec
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依托单位:
MECHANISMS OF AUTOIMMUNE ARTHRITIS
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批准号:6171643
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项目类别:
-
资助金额:$18.55万
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财政年份:1998
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负责人:Edward F Rosloniec
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依托单位:
ROLE OF IA EPITOPES IN ANTIGEN PRESENTATION
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批准号:3029954
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项目类别:
-
资助金额:$2.6万
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财政年份:1988
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负责人:Edward F Rosloniec
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依托单位:
ROLE OF IA EPITOPES IN ANTIGEN PRESENTATION
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批准号:3029955
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项目类别:
-
资助金额:$0.68万
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财政年份:1988
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负责人:Edward F Rosloniec
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依托单位:
海外基金