Effector-Regulator Immune Interactions During Autoimmune Demyelinating Disease

自身免疫性脱髓鞘疾病期间效应器-调节器免疫相互作用

• 批准号: 10595509
• 负责人: NITIN J KARANDIKAR
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10595509
• 关键词: Acute; Address; Affect; American; Animal Model; Antigen-Presenting Cells; Arthritis; Autoimmune; Autoimmune Diseases; Autoimmunity; Biological Response Modifiers; Biology; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Clinical; Communicable Diseases; Demyelinating Diseases; Disease; Dissection; Experimental Autoimmune Encephalomyelitis; Feedback; Future; Goals; Healthcare; Human; Hypersensitivity; IL17 gene; IL2RA gene; Immune; Immune system; Immunosuppression; Immunotherapeutic agent; In Vitro; Inflammatory; Insulin-Dependent Diabetes Mellitus; Interleukin-12; Interleukin-6; Intervention; Malignant Neoplasms; Mediating; Memory; Modeling; Molecular Profiling; Multiple Sclerosis; Mus; PPBP gene; Pathogenesis; Pathogenicity; Pathway interactions; Peripheral Blood Mononuclear Cell; Persons; Phenotype; Process; Publications; Publishing; Recurrent disease; Relapse; Resistance; Role; STAT3 gene; Stimulus; T cell differentiation; T cell response; T-Lymphocyte; TC1 Cell; Th1 Cells; Therapeutic; Therapeutic Intervention; Time; Veterans; Work; central nervous system demyelinating disorder; comparison control; cytokine; cytotoxicity; effector T cell; functional plasticity; immunopathology; immunoregulation; in vivo; insight; interest; multiple sclerosis patient; novel; receptor; transcriptome; transcriptome sequencing

Multiple sclerosis (MS) is an inflammatory, demyelinating disorder of the central nervous system (CNS) that affects over 1 million people in the US. T-cell-driven immunopathology is a central feature of MS and other immune-mediated diseases. As a consequence, the immune regulation of these pathogenic T-cell responses is an important quest in the approach to autoimmunity. We have had a long-standing interest in the immune basis of human multiple sclerosis (MS) and its animal model (EAE). While the pathogenic role of CD4 T-cells is well established in these diseases, there is growing evidence from us and others for a role of CD8 T-cells in these diseases. Through studies in MS and EAE, we have demonstrated the critical disease regulatory role of CD8 T-cells in disease. Similar appreciation for the role of these cells in downregulating other autoimmune diseases has also emerged. We have also shown that the suppressor activity of MS relapse-associated CD8 T-cells can be restored by in vitro pre-treatment with specific cytokines, revealing functional plasticity of these cells and providing a potential avenue for therapeutic intervention. At the same time, it is also becoming clear that severe autoimmune disease is characterized by increased resistance of effector/pathogenic CD4 T-cells to immune regulation. Collectively, these studies underscore the importance of understanding both the biology of CD4 effector T-cell resistance to suppression as well as the intricacies of CD8 suppression and its modulation. Our proposal addresses this poorly understood but fundamental feature of the immune regulatory apparatus, in the context of MS. Our recent studies demonstrate several novel aspects of the CD4-CD8 effector-regulator dynamics and based on these findings, we hypothesize that CD4 T-cells from MS patients have an intrinsically enhanced tendency to develop effector resistance to immune suppression in an inflammatory context, while CD8 T-cells from MS patients have an intrinsically enhanced tendency to develop lower suppressive ability. We also hypothesize that these phenotypes are plastic and can be modulated by appropriate stimuli. To address these hypotheses, we will use a two-pronged approach: (1) We will address the biology and modulation of CD4 resistance in MS to gain direct insights into these processes in the context of autoimmune disease. A part of this aim will also focus on the novel CD4-intrinsic biology of IL-17 cytokines, as demonstrated in our recent publication; and (2) We will also address the biology and modulation of CD8 suppression in MS. These studies will provide important insights into the immune dysregulation that underlies MS pathogenesis, with implications for treatment approaches in MS and multiple other disease settings.

多发性硬化症 (MS) 是一种中枢神经系统 (CNS) 炎症性脱髓鞘疾病， 影响美国超过100万人。 T 细胞驱动的免疫病理学是 MS 和其他疾病的核心特征 免疫介导的疾病。因此，这些致病性 T 细胞反应的免疫调节是 自身免疫方法中的一个重要探索。我们长期以来对免疫基础很感兴趣 人类多发性硬化症（MS）及其动物模型（EAE）。虽然 CD4 T 细胞的致病作用已被充分证实 我们和其他人越来越多的证据表明 CD8 T 细胞在这些疾病中发挥作用 疾病。通过对 MS 和 EAE 的研究，我们证明了 CD8 的关键疾病调节作用 疾病中的 T 细胞。对这些细胞在下调其他自身免疫性疾病中的作用也有类似的认识 疾病也随之出现。我们还表明 MS 复发相关的 CD8 的抑制活性 T细胞可以通过特定细胞因子的体外预处理来恢复，揭示了T细胞的功能可塑性 这些细胞并为治疗干预提供了潜在的途径。同时，它也是 越来越清楚的是，严重的自身免疫性疾病的特点是抵抗力增加 效应/致病性 CD4 T 细胞对免疫调节的影响。总的来说，这些研究强调 了解 CD4 效应 T 细胞对抑制的生物学抵抗力的重要性 CD8 抑制及其调节的复杂性。我们的提案没有很好地解决这个问题 在多发性硬化症的背景下，免疫调节装置的基本特征已被理解。我们的 最近的研究证明了 CD4-CD8 效应调节器动力学的几个新颖方面，并基于 根据这些发现，我们假设来自多发性硬化症患者的 CD4 T 细胞具有内在增强的倾向 在炎症环境中对免疫抑制产生效应抵抗，而来自多发性硬化症的 CD8 T 细胞 患者本质上具有增强的抑制能力降低的倾向。我们还假设 这些表型是可塑的，可以通过适当的刺激进行调节。为了解决这些假设， 我们将采用双管齐下的方法：（1）我们将解决 MS 中 CD4 耐药性的生物学和调节问题 直接了解自身免疫性疾病背景下的这些过程。这一目标的一部分也将 重点关注 IL-17 细胞因子的新型 CD4 内在生物学，如我们最近发表的出版物所示；和（2） 我们还将讨论 MS 中 CD8 抑制的生物学和调节。这些研究将提供 对多发性硬化症发病机制中免疫失调的重要见解，对 多发性硬化症和多种其他疾病的治疗方法。