Effects of EBV on autoimmunity and responses to immune therapy

总结 爱泼斯坦巴尔病毒（EBV）已被认为是自身免疫性疾病的致病或疾病修饰剂。 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 他人然而，尽管有这些公认的联系，这种病毒感染可以触发的机制， 或修改自身免疫性尚未确定。一些研究人员发现， 靶点和EBV，而其他研究人员已经描述了免疫库的变化， 自身免疫的进展。1型糖尿病（T1 D）以前与EBV感染无关。 然而，在最近完成的teplizumab（一种FcR非结合人源化抗CD 3 mAb）试验中， 我们发现，药物治疗是否会延迟高风险非糖尿病亲属（TN 10）的T1 D诊断， 研究入组时EBV血清阳性患者的药物疗效优于EBV血清阳性患者， 血清。EBV血清阳性对替利珠单抗应答的影响， CMV阳性和阴性的患者进行比较。此外，我们发现， 既往在新发T1 D（AbATE）患者中进行的替利珠单抗随机试验中， EBVsero+与EBVsero-参与者的比较。对替利珠单抗的免疫应答与 诱导部分耗竭的CD 8+记忆（CD 45 RO+）T细胞，其通过共表达 KLRG 1和TIGIT。在TN 10和AbATE试验中，这些细胞的频率在EBVsero+中更高。 与基线和药物治疗后的血清个体相比，表明EBV对塑造免疫系统的影响。 库和改变T细胞对抗CD 3 mAb的应答。在本提案中，我们将检验以下假设： 当teplizumab治疗T1 D时，EBV调节免疫应答，增强T1 D的保护和进展 给出了我们将分析TN 10参与者中T和B细胞的转录组，并分析其差异。 EBV血清阳性与阴性个体之间的差异，并分析这些数据，同时计数EBV反应性T细胞， 细胞EB病毒潜伏在B细胞中，我们将检验病毒对B细胞的作用可能增强免疫应答的假设。 Teplizumab的活性。最后，为了进一步了解B细胞与潜伏EBV和T细胞之间的关系， 在T1 D中，我们将测试抗CD 20 mAb去除B细胞是否降低了T细胞的频率， 使用来自新发T1 D（TN 05）中的利妥昔单抗试验的样品的耗尽表型。使用这些设置 免疫紊乱，我们希望确定T/B细胞的相互作用，是由EB病毒的影响，不能 在稳定状态下得到赞赏。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。

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.