Immune Dysregulation During Multiple Sclerosis Relapse

多发性硬化症复发期间的免疫失调

• 批准号: 9929670
• 负责人: NITIN J KARANDIKAR
• 金额: $ 14.65万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-19 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9929670
• 关键词: Acute; Acute Disease; Address; Affect; Animal Model; Anti-inflammatory; Antigens; Autoimmune Process; B-Lymphocytes; Biology; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Adhesion Molecules; Cells; Cellular biology; Characteristics; Clinical; Defect; Demyelinations; Disease; Dissection; Experimental Autoimmune Encephalomyelitis; Future; Goals; Granzyme; Histology; Human; Immune; Immune response; Immunologic Monitoring; Immunologics; Immunology; Immunotherapeutic agent; Immunotherapy; In Vitro; Inflammatory; Institution; Interferon Type II; Interleukin-12; Longitudinal Studies; Mediating; Modeling; Multiple Sclerosis; Myelin; Neuraxis; Pathogenesis; Patient Monitoring; Patient Recruitments; Patients; Population; Process; Publishing; Recurrent disease; Regulatory T-Lymphocyte; Relapse; Reporting; Resistance; Role; Steroid therapy; Steroids; T cell response; T-Lymphocyte; autoreactive T cell; base; central nervous system demyelinating disorder; chemokine receptor; cytokine; effector T cell; immunopathology; immunoregulation; innovation; insight; novel; novel therapeutic intervention; perforin; recruit; response

Project Summary/Abstract Multiple sclerosis (MS) is an inflammatory, demyelinating disorder of the central nervous system that affects over 400,000 people in the US. The most common clinical form of MS presents with a relapsing-remitting clinical course (RRMS). Whereas several immune differences have been shown between RRMS patients and healthy subjects, the immunologic basis of a clinical relapse remains poorly understood. Some studies have shown aberrant immune responses to myelin antigens and defect in regulatory T and B cells during an acute disease relapse. However, the immune dysregulation that underlies the relapse remains unclear. In particular, there is a paucity of longitudinal studies addressing CD4 and CD8 T cell effector and regulatory responses before, during and after an acute relapse. Using innovative approaches, our recent studies have made several interesting observations relating to CD4 and CD8 regulatory T cell biology during acute relapse of MS. We have demonstrated the novel and unexpected immune regulatory function of CNS-specific CD8+ T cells. Interestingly, RRMS patients with quiescent disease and healthy subjects showed comparable levels of CNS-specific CD8 suppressor activity. However, patients during an acute relapse showed a dramatic deficit of CNS-specific suppressor activity, even when CNS-specific CD8 responses could be detected at pre-relapse level. Moreover, as patients attained disease quiescence [with various different therapies], they consistently showed normalization of CNS-specific CD8 suppressor activity. We have further observed that these deficits are correctable by modulation of the cytokine milieu and through understanding of the mechanisms through which immune regulation is achieved. In recent unpublished studies, we have also shown the dysregulation of a novel sub-population of induced CD4+ regulatory T cells during an acute MS relapse. Based on these findings, we hypothesize that an accumulating longitudinal deficit of immune regulatory function and effector resistance results in an MS relapse. As a corollary, we predict that correcting these functional deficits is an important immunologic correlate of disease quiescence. Through the proposed studies, we will address these hypotheses by delineating the longitudinal fluctuation of CD4 and CD8 regulatory ability and its relationship with an MS relapse. We will dissect the various mechanisms of relapse- associated CD8 regulatory deficit and attempt to devise strategies to correct the observed deficits. The proposed studies will provide greater fundamental insights into the immunologic processes underlying disease relapse with the potential for novel immunotherapeutic strategies.

项目摘要/摘要 多发性硬化症(MS)是一种炎症性、脱髓鞘的中枢神经系统疾病，影响 美国有超过40万人。多发性硬化症最常见的临床表现为复发-缓解 临床疗程(RRMS)。而在RRMS患者和RRMS患者之间显示出几个免疫差异 在健康受试者中，临床复发的免疫学基础仍然知之甚少。一些研究表明 表现出对髓鞘抗原的异常免疫反应和调节性T和B细胞缺陷 疾病复发。然而，复发背后的免疫失调仍不清楚。特别是， 针对CD4和CD8T细胞效应器和调节性反应的纵向研究很少 在急性复发之前、期间和之后。使用创新的方法，我们最近的研究取得了 急性复发期间与CD4和CD8调节性T细胞生物学相关的几个有趣的观察 我们已经证明了CNS特异性CD8+T细胞的新的和意想不到的免疫调节功能 细胞。有趣的是，患有静止期疾病的RRMS患者和健康受试者显示出相似的水平 中枢神经系统特异性CD8抑制子活性。然而，在急性复发期间，患者表现出戏剧性的 中枢神经系统特异性抑制因子活性缺失，即使可以检测到中枢神经系统特异性CD8反应也是如此 在复发前水平。此外，当患者[通过各种不同的治疗方法]达到疾病平静时， 它们始终显示出CNS特异性CD8抑制活性的正常化。我们进一步观察到 这些缺陷是可以通过调节细胞因子环境和通过理解 实现免疫调节的机制。在最近未发表的研究中，我们还 显示在急性多发性硬化症期间诱导的一种新的CD4+调节性T细胞亚群的失调 旧病复发。基于这些发现，我们假设免疫系统的纵向累积缺陷 调节功能和效应器抵抗导致MS复发。作为推论，我们预测 纠正这些功能缺陷是疾病平静的一个重要的免疫学相关性。通过 建议的研究，我们将通过描绘CD4和CD8的纵向波动来解决这些假设 调节能力及其与多发性硬化复发的关系。我们将剖析复发的各种机制- 与CD8相关的监管缺陷，并试图制定策略来纠正观察到的缺陷。这个 拟议的研究将为疾病背后的免疫过程提供更基本的见解。 复发与新的免疫治疗策略的潜力。