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
• 负责人: Nora E Sarvetnick
• 金额: $ 72.87万
• 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 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10468752
• 关键词: Advocate; Antigens; Antiviral Response; Antiviral Therapy; Autoantibodies; Autoimmune; Autoimmune Diseases; 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 虽然环保实体煽动T1 D开发，但他们的身份尚不清楚。遗传学大大增加了 风险，但同卵双胞胎之间的不一致证明了外源因素同样重要的作用。以识别 对于致病实体，采样必须在临床疾病发展之前进行。虽然劳动密集型和昂贵的， 前瞻性纵向测试是阐明疾病前神秘事件的唯一途径。结果 从我们最近与TrialNet预防途径研究的合作中， T1 D发展中的感染我们发现了一个惊人的扩大终末分化的短寿命效应 血清转化（AA+）高危受试者中的CD 8 T细胞（SLEC）。SLEC的频率最高， 血清转化的受试者进展为疾病。该SLEC子集与表征良好的 CD 8对CMV的应答。重要的是，我们发现SLEC扩增与CMV密切相关， 血清阳性我们的研究结果表明，一个扩大的，用尽抗病毒反应发生在一个 在自身免疫性T1 D发病前一年。我们还确定SLEC水平与IA-2密切相关， 自身抗体，表明CMV和自身免疫之间的联系。自身反应性T1 D结果 CD 8 T细胞介导的对胰岛的攻击。这些自身反应性T细胞可能是抗- 病毒反应我们的总体假设是CMV是加速T1 D的重要环境因素 有遗传风险的儿童。本申请的目的是纵向探测 临床前疾病的过程，并解开连接CMV和T1 D的机制。在目标1中，我们提出 通过纵向研究得出动力学测量值。我们假设遗传易感 前T1 D儿童在发展前表现出增加的耗尽的CD 8 T细胞水平， 自身抗体和/或临床自身免疫。在目标2中，我们将测量CMV复制和持久性， 自身免疫性疾病的高危人群我们假设耗尽的CD 8 T细胞的积累 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CD 8 T细胞的机制。 细胞我们假设CMV感染诱导胰岛抗原特异性CD 8 T细胞的扩增。一个 CMV复制和T1 D之间已建立的联系将表明抗病毒治疗在治疗T1 D中有效。 高遗传风险的人。此外，CMV复制水平和SLEC代表连锁 生物标志物，用于对抗病毒和/或疫苗试验的受试者进行分层。几种CMV疫苗目前正在 在诊所测试。我们的研究结果也将有助于了解其他CMV相关的人类疾病。