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
• 负责人: Nora E Sarvetnick
• 金额: $ 73.35万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10021542
• 关键词: Advocate; Antigens; Antiviral Agents; Antiviral Response; Antiviral Therapy; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Biological Markers; C-Peptide; CD8-Positive T-Lymphocytes; CD8B1 gene; Cesarean section; Child; Clinic; Clinical; Collaborations; Coxsackie Viruses; Cytomegalovirus; Cytomegalovirus Infections; Cytomegalovirus Vaccines; Detection; Development; Disease; Environmental Risk Factor; Etiology; Event; Exogenous Factors; Frequencies; Genetic; Genetic Risk; Haplotypes; Human; Hygiene; IA-2-autoantibody; Infection; Insulin-Dependent Diabetes Mellitus; Investigation; Islets of Langerhans; Kinetics; Longitudinal Studies; Measurement; Measures; Mediating; Microbiology; Monozygotic twins; Nutrient; PTPN22 gene; Pathway interactions; Prevention; Process; Reagent; Reporting; Risk; Role; Sampling; Siblings; Specificity; Sunlight; T-Lymphocyte; TNFRSF10A gene; Testing; Variant; Viral; Viral Proteins; Virus; Virus Diseases; Virus Replication; Work; antigen-specific T cells; autoreactive T cell; autoreactivity; chronic infection; cost; diabetes risk; environmental agent; exhaust; genetic risk factor; human disease; islet; microbiome; pre-clinical; preclinical development; prevent; prospective; response; seroconversion; seropositive; vaccine trial

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 虽然环境实体煽动了T1D的发展，但他们的身份尚不清楚。遗传学大大增加 风险，但同卵双胞胎之间的不一致被证明对外部因素同样重要。要确定 对于因果实体，抽样必须在临床疾病发生之前进行。虽然劳动密集型且成本高昂， 前瞻性纵向测试是阐明疾病发生前的神秘事件的唯一途径。结果 从我们最近与TrialNet路径到预防的合作研究指出CMV的作用 T1D发育中的感染。我们发现了终末分化的短命效应器的显著扩张 血清转换(AA+)高危人群的CD8 T细胞(SLEC)。SLEC的频率最高的是 血清转换的受试者会发展成疾病。这个SLEC子集与刻画得很好的 CD8对CMV的应答。重要的是，我们发现SLEC的扩张与CMV密切相关 血清阳性。我们的发现表明，一种扩大的、疲惫的抗病毒反应发生在 在自身免疫性T1D发生前一年。我们还确定SLEC水平与IA-2密切相关 自身抗体，证明了巨细胞病毒和自身免疫之间的联系。自身反应导致的T1D结果 CD8T细胞介导的胰岛攻击。这些自身反应性T细胞可能是抗-HBs的副产物 病毒反应。我们的主要假设是，CMV是加速T1D的重要环境因素 有遗传风险的儿童的发育。这个应用程序的目标是纵向探索 临床前疾病过程和揭示CMV和T1D之间的联系机制。在目标1中，我们建议 通过纵向研究得出动力学测量结果。我们假设遗传易感性 T1D前期儿童在发展为T1D之前，其耗尽的CD8 T细胞水平升高 自身抗体和/或临床自身免疫。在目标2中，我们将测量CMV的复制和持久性 患上自身免疫力的高危人群。我们假设耗尽的CD8 T细胞的积聚 导致病毒持续存在。在目标3中，我们将测试病毒激活胰岛特异性CD8T的机制 细胞。我们假设CMV感染诱导了胰岛抗原特异性CD8T细胞的增殖。一个 在CMV复制和T1D之间建立的联系将表明抗病毒疗法在 具有高遗传风险的受试者。此外，CMV复制和SLEC的水平代表互锁 用于抗病毒和/或疫苗试验的分层受试者的生物标记物。几种巨细胞病毒疫苗目前正在研发中 在诊所里做了测试。我们的结果也将有助于理解其他与CMV相关的人类疾病。