CMV responses in autoantibody positive subjects advocate antiviral treatments for prevention of T1D
自身抗体阳性受试者的 CMV 反应主张抗病毒治疗以预防 T1D
基本信息
- 批准号:10230365
- 负责人:
- 金额:$ 6.31万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-05-19 至 2023-08-31
- 项目状态:已结题
- 来源:
- 关键词:AdvocateAntigensAntiviral AgentsAntiviral ResponseAntiviral TherapyAutoantibodiesAutoimmune DiseasesAutoimmune ProcessAutoimmunityBiological MarkersC-PeptideCD8-Positive T-LymphocytesCD8B1 geneCesarean sectionChildClinicClinicalCollaborationsCoxsackie VirusesCytomegalovirusCytomegalovirus InfectionsCytomegalovirus VaccinesDetectionDevelopmentDiseaseEnvironmental Risk FactorEtiologyEventExogenous FactorsFrequenciesGeneticGenetic RiskHaplotypesHumanHygieneIA-2-autoantibodyInfectionInsulin-Dependent Diabetes MellitusInvestigationIslets of LangerhansKineticsLongitudinal StudiesMeasurementMeasuresMediatingMicrobiologyMonozygotic twinsNutrientPTPN22 genePathway interactionsPreventionProcessReagentReportingRiskRoleSamplingSiblingsSpecificitySunlightT-LymphocyteTNFRSF10A geneTestingVariantViralViral ProteinsVirusVirus DiseasesVirus ReplicationWorkantigen-specific T cellsautoreactive T cellautoreactivitychronic infectioncostdiabetes riskenvironmental agentexhaustgenetic risk factorhuman diseaseisletmicrobiomepre-clinicalpreclinical developmentpreventprospectiveresponseseroconversionseropositivevaccine trial
项目摘要
Project Abstract
While environmental entities instigate T1D development, their identity is unknown. Genetics greatly increases
risk, but the discordance between identical twins proves an equally critical role for exogenous factors. To identify
causal entities, sampling must occur before clinical disease develops. Although labor intensive and costly,
prospective longitudinal testing is the only way to illuminate the mysterious events that precede disease. Results
from our recent collaboration with the TrialNet Pathway to Prevention study point to a role for CMV
infection in T1D development. We found a striking expansion of terminally-differentiated short lived effector
CD8 T cells (SLEC) in seroconverted (AA+) at-risk subjects. The frequencies of SLEC are highest in
seroconverted subjects that progress to disease. This SLEC subset is identical to the well-characterized
CD8 response to CMV. Importantly, we found the SLEC expansion is strongly associated with CMV
seropositivity. Our findings demonstrate that an expanded, exhausted antiviral response occurs one
year before autoimmune T1D develops. We also determined that SLEC levels correlate strongly with IA-2
autoantibodies, demonstrating a connection between CMV and autoimmunity. T1D results from autoreactive
CD8 T cell-mediated attack on pancreatic islets. These autoreactive T cells may arise as a byproduct of the anti-
viral response. Our overarching hypothesis is that CMV is an important environmental factor accelerating T1D
development in children with genetic risk. The objective of this application is to longitudinally probe the
preclinical disease process and unravel the mechanisms connecting CMV and T1D. In Aim 1 we propose
to derive kinetic measurements through a longitudinal study. We hypothesize that genetically susceptible
pre-T1D children show increased levels of exhausted CD8 T cells prior to the development of
autoantibodies and/or clinical autoimmunity. In aim 2 we will measure CMV replication and persistence in at
risk subjects that develop autoimmunity. We hypothesize that the accumulation of exhausted CD8 T cells
causes viral persistence. In aim 3 we will test mechanisms whereby the virus activates islet specific CD8 T
cells. We hypothesize that CMV infection induces the expansion of islet antigen-specific CD8 T cells. An
established connection between CMV replication and T1D will point to antiviral therapies as efficacious in
subjects with high genetic risk. Furthermore, levels of CMV replication and SLEC represent interlocking
biomarkers for stratifying subjects for antiviral and/or vaccine trials. Several CMV vaccines are currently being
tested in the clinic. Our results will also facilitate the understanding of other CMV-related human diseases.
项目摘要
项目成果
期刊论文数量(0)
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Nora E Sarvetnick其他文献
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{{ truncateString('Nora E Sarvetnick', 18)}}的其他基金
CMV responses in autoantibody positive subjects advocate antiviral treatments for prevention of T1D
自身抗体阳性受试者的 CMV 反应主张抗病毒治疗以预防 T1D
- 批准号:
9917451 - 财政年份:2019
- 资助金额:
$ 6.31万 - 项目类别:
CMV responses in autoantibody positive subjects advocate antiviral treatments for prevention of T1D
自身抗体阳性受试者的 CMV 反应主张抗病毒治疗以预防 T1D
- 批准号:
10468752 - 财政年份:2019
- 资助金额:
$ 6.31万 - 项目类别:
CMV responses in autoantibody positive subjects advocate antiviral treatments for prevention of T1D
自身抗体阳性受试者的 CMV 反应主张抗病毒治疗以预防 T1D
- 批准号:
10021542 - 财政年份:2019
- 资助金额:
$ 6.31万 - 项目类别:
CMV responses in autoantibody positive subjects advocate antiviral treatments for prevention of T1D
自身抗体阳性受试者的 CMV 反应主张抗病毒治疗以预防 T1D
- 批准号:
10239082 - 财政年份:2019
- 资助金额:
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Uncovering pathogenic anti-bacterial defense mechanisms to identify novel targets for prevention of T1D
揭示致病性抗菌防御机制以确定预防 T1D 的新靶点
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10207399 - 财政年份:2017
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Cytokine receptor populations in human autoimmune diabetes
人类自身免疫性糖尿病中的细胞因子受体群体
- 批准号:
8499253 - 财政年份:2012
- 资助金额:
$ 6.31万 - 项目类别:
Cytokine receptor populations in human autoimmune diabetes
人类自身免疫性糖尿病中的细胞因子受体群体
- 批准号:
8681355 - 财政年份:2012
- 资助金额:
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Cytokine receptor populations in human autoimmune diabetes
人类自身免疫性糖尿病中的细胞因子受体群体
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9096009 - 财政年份:2012
- 资助金额:
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Cytokine receptor populations in human autoimmune diabetes
人类自身免疫性糖尿病中的细胞因子受体群体
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8374068 - 财政年份:2012
- 资助金额:
$ 6.31万 - 项目类别:
Are IL-18 receptor-bearing CD8 T cells pathogenic in human Type 1 diabetes?
携带 IL-18 受体的 CD8 T 细胞在人类 1 型糖尿病中是否致病?
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8313163 - 财政年份:2011
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