Effects of EBV on autoimmunity and responses to immune therapy

EBV 对自身免疫和免疫治疗反应的影响

• 批准号: 10493414
• 负责人: Kevan C Herold
• 金额: $ 20.94万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-22 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10493414
• 关键词: Abate; Affect; Aftercare; Age; Antigens; Autoantibodies; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; C-Peptide; CD3 Antigens; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Communication; Cells; Chronic; Clinical; Clinical Trials; Cytomegalovirus; Data; Data Analyses; Development; Diabetes Mellitus; Diagnosis; Disease; Epstein-Barr Virus Infections; Epstein-Barr Virus latency; Exposure to; Flow Cytometry; Frequencies; Goals; Human; Human Herpesvirus 4; Immune; Immune Response Genes; Immune Tolerance; Immune response; Immunologics; Immunotherapy; Impairment; Individual; Infection; Insulin-Dependent Diabetes Mellitus; Investigation; Lead; Memory; Modeling; Modification; Molecular; Monoclonal Antibodies; Multiple Sclerosis; Mus; Participant; Patients; Peripheral; Pharmacotherapy; Phenotype; Plasma Cells; Proteins; Research Personnel; Rheumatoid Arthritis; Role; Sampling; Shapes; Systemic Lupus Erythematosus; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Time; Tissues; Transcript; Tropism; Viral; Virus; Virus Diseases; Virus Latency; adaptive immune response; anti-CD20; autoreactive T cell; clinical diagnosis; cross reactivity; drug efficacy; exhaust; exhaustion; high risk; humanized mouse; immunoregulation; insulin dependent diabetes mellitus onset; multiple sclerosis patient; non-diabetic; precision medicine; prevent; randomized trial; response; restoration; rituximab; seropositive; single-cell RNA sequencing; transcription factor; transcriptome

Summary Epstein Barr Virus (EBV) has been incriminated as a causative or disease modifying agent in autoimmune diseases including multiple sclerosis (MS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and others. Yet despite these well recognized associations, the mechanisms whereby this viral infection can trigger or modify autoimmunity have not been identified. Some investigators have found shared antigens between tissue targets and EBV while other investigators have described changes to the immune repertoire that may affect progression of autoimmunity. Type 1 diabetes (T1D) has not previously been associated with EBV infection. However, in the recently completed teplizumab (a FcR non-binding humanized anti-CD3 mAb) trial, to test whether drug treatment would delay the diagnosis of T1D in non-diabetic relatives at high-risk (TN10), we found that the drug efficacy was better in those who were EBV sero+ at study entry compared to those who were EBV sero-. The effect of EBV seropositivity on the response to teplizumab and was not seen when individuals who were CMV+ and – were compared. In addition, we found that there was a significant improvement in retention of C-peptide in a previous randomized trial of teplizumab in patients with new onset T1D (AbATE) among EBVsero+ compared to EBVsero- participants. Immune response to teplizumab have been associated with induction of partially exhausted CD8+ memory (CD45RO+) T cells which are identified by co-expression of KLRG1 and TIGIT. In both the TN10 and AbATE trials the frequency of these cells was higher in the EBVsero+ vs sero- individuals at the baseline and after drug treatment suggesting an effect of EBV on shaping the immune repertoire and in altering T cellular responses to anti-CD3 mAb. In this proposal we will test the hypothesis that EBV modulates immune responses that enhance the protection from and progression of T1D when teplizumab is given. We will analyze the transcriptome of T and B cells in the TN10 participants and analyze the differences between EBV sero+ vs – individuals and analyzing these data together with enumerating the EBV reactive T cells. EBV is latent in B cells and we will test the hypothesis that the virus’ effects on B cells may enhance the activity of teplizumab. Finally, to further understand the relationship between B cells with latent EBV and T cells in T1D, we will test whether B cell depletion with anti-CD20 mAb reduces the frequency of T cells with a partially exhausted phenotype using samples from the Rituximab trial in new onset T1D (TN05). Using these settings of immune disturbances, we expect to identify T/B cell interactions that are affected by EBV that cannot be appreciated under steady state conditions. The mechanisms that we identify have broad application to understanding several autoimmune diseases and in identifying mechanisms of action of immune therapy.

概括 EB 病毒 (EBV) 已被认为是自身免疫性疾病的致病因素或疾病调节剂 疾病包括多发性硬化症（MS）、类风湿性关节炎（RA）、系统性红斑狼疮（SLE）和 其他的。然而，尽管有这些众所周知的关联，但这种病毒感染引发的机制 或改变自身免疫尚未确定。一些研究人员发现组织之间存在共享抗原 目标和 EBV，而其他研究人员已经描述了可能影响免疫组库的变化 自身免疫的进展。 1 型糖尿病 (T1D) 此前并未与 EBV 感染相关。 然而，在最近完成的 teplizumab（一种 FcR 非结合人源化抗 CD3 mAb）试验中，测试 我们发现药物治疗是否会延迟非糖尿病高危亲属 (TN10) 的 T1D 诊断 与 EBV 患者相比，研究开始时 EBV 血清 + 患者的药物疗效更好 血清-. EBV 血清阳性对 teplizumab 反应的影响在以下个体中并未观察到： 比较了 CMV+ 和 – 。此外，我们发现保留率有了显着提高 之前一项针对新发 T1D (AbATE) 患者的 teplizumab 随机试验中 C 肽的变化 EBVsero+ 与 EBVsero- 参与者相比。对特普利珠单抗的免疫反应与 诱导部分耗尽的 CD8+ 记忆 (CD45RO+) T 细胞，其通过共表达来识别 KLRG1 和 TIGIT。在 TN10 和 AbATE 试验中，这些细胞在 EBVsero+ 中的出现频率较高 与血清个体在基线和药物治疗后的比较表明 EBV 对塑造免疫的影响 库并改变 T 细胞对抗 CD3 mAb 的反应。在这个提案中，我们将测试以下假设： 当特普利珠单抗使用时，EBV 调节免疫反应，增强对 T1D 的保护和进展 被给出。我们将分析TN10参与者的T细胞和B细胞转录组并分析差异 EBV sero+ 与 – 个体之间的比较，并分析这些数据并枚举 EBV 反应性 T 细胞。 EBV 潜伏在 B 细胞中，我们将检验该病毒对 B 细胞的影响可能会增强 B 细胞的假设。 特普利珠单抗的活性。最后，进一步了解潜伏EBV的B细胞与T细胞的关系 在 T1D 中，我们将测试用抗 CD20 mAb 消除 B 细胞是否会降低 T 细胞的频率 使用来自新发 T1D (TN05) 的 Rituximab 试验的样本显示耗尽表型。使用这些设置 免疫紊乱，我们希望能够识别出受 EBV 影响的 T/B 细胞相互作用，而这些相互作用是无法被 在稳态条件下升值。我们确定的机制具有广泛的应用 了解几种自身免疫性疾病并确定免疫治疗的作用机制。