Immune Dysregulation During Multiple Sclerosis Relapse

多发性硬化症复发期间的免疫失调

基本信息

批准号：
9915848
负责人：
NITIN J KARANDIKAR
金额：
$ 73.25万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-19 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9915848
关键词：
Acute Acute Disease Address Affect Animal Model Anti-Inflammatory Agents 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

项目摘要

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.

项目概要/摘要多发性硬化症 (MS) 是一种中枢神经系统炎症性脱髓鞘疾病，影响美国有超过 400,000 人。 MS 最常见的临床形式表现为复发缓解型临床过程（RRMS）。鉴于 RRMS 患者和 RRMS 患者之间已显示出一些免疫差异对于健康受试者，临床复发的免疫学基础仍然知之甚少。一些研究有在急性发作期间表现出对髓磷脂抗原的异常免疫反应以及调节性 T 和 B 细胞的缺陷疾病复发。然而，复发背后的免疫失调仍不清楚。尤其，针对 CD4 和 CD8 T 细胞效应和调节反应的纵向研究很少急性复发之前、期间和之后。我们最近的研究采用创新方法急性复发期间与 CD4 和 CD8 调节性 T 细胞生物学相关的几个有趣的观察结果女士。我们已经证明了 CNS 特异性 CD8+ T 具有新颖且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 患者和健康受试者表现出相当的水平 CNS 特异性 CD8 抑制活性。然而，急性复发期间的患者表现出戏剧性的变化。 CNS 特异性抑制活性不足，即使可以检测到 CNS 特异性 CD8 反应处于复发前水平。此外，当患者[通过各种不同的疗法]达到疾病静止状态时，它们始终表现出中枢神经系统特异性 CD8 抑制活性的正常化。我们进一步观察到这些缺陷可以通过调节细胞因子环境和了解实现免疫调节的机制。在最近未发表的研究中，我们还显示了急性多发性硬化症期间诱导的 CD4+ 调节性 T 细胞的新亚群的失调复发。基于这些发现，我们假设免疫的纵向缺陷不断累积调节功能和效应子抵抗会导致多发性硬化症复发。作为推论，我们预测纠正这些功能缺陷是疾病静止的重要免疫相关因素。通过拟议的研究中，我们将通过描述 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症复发的关系。我们将剖析各种复发机制—— 相关的 CD8 监管缺陷并尝试制定策略来纠正观察到的缺陷。这拟议的研究将为疾病潜在的免疫过程提供更深入的基础见解复发具有新的免疫治疗策略的潜力。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

IL-12-Induced Immune Suppressive Deficit During CD8+ T-Cell Differentiation.

CD8 T 细胞分化过程中 IL-12 诱导的免疫抑制缺陷。

DOI：
发表时间：
2020
期刊：
影响因子：
0
作者：
Renavikar, Pranav S;Sinha, Sushmita;Brate, Ashley A;Borcherding, Nicholas;Crawford, Michael P;Steward;Karandikar, Nitin J
通讯作者：
Karandikar, Nitin J

An autoimmune disease risk SNP, rs2281808, in SIRPG is associated with reduced expression of SIRPγ and heightened effector state in human CD8 T-cells.

SIRPG 中的自身免疫性疾病风险 SNP rs2281808 与 SIRPγ 表达减少和人类 CD8 T 细胞中效应器状态升高相关。

DOI：
发表时间：
2018
期刊：
影响因子：
4.6
作者：
Sinha, Sushmita;Borcherding, Nicholas;Renavikar, Pranav S;Crawford, Michael P;Tsalikian, Eva;Tansey, Michael;Shivapour, Ezzatollah T;Bittner, Frank;Kamholz, John;Olalde, Heena;Gibson, Emilee;Karandikar, Nitin J
通讯作者：
Karandikar, Nitin J

Disruption of IFNγ, GZMB, PRF1, or LYST Results in Reduced Suppressive Function in Human CD8+ T Cells.

IFNγ、GZMB、PRF1 或 LYST 的破坏会导致人 CD8 T 细胞的抑制功能降低。