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）是中枢神经系统（CNS）的炎症性脱髓鞘疾病 在美国影响超过100万人。 T细胞驱动的免疫病理学是MS和其他其他 免疫介导的疾病。结果，这些致病性T细胞反应的免疫调节是 在自身免疫方法中的重要追求。我们在免疫基础上长期存在兴趣 人类多发性硬化症（MS）及其动物模型（EAE）。虽然CD4 T细胞的致病作用很好 在这些疾病中建立，我们和其他人越来越有证据表明CD8 T细胞在这些中的作用 疾病。通过在MS和EAE中的研究，我们证明了CD8的关键疾病调节作用 疾病的T细胞。对这些细胞在下调其他自身免疫性中的作用的类似欣赏 疾病也出现了。我们还表明，MS复发相关CD8的抑制活性 可以通过特定细胞因子的体外预处理来恢复T细胞，从而揭示了功能可塑性 这些细胞并为治疗干预提供了潜在的途径。同时，也是 很明显，严重的自身免疫性疾病的特征是增加 效应子/致病性CD4 T细胞以进行免疫调节。总的来说，这些研究强调了 了解CD4效应的生物学T细胞对抑制的抗性的重要性 作为CD8抑制的复杂性及其调节。我们的建议解决了这一问题 在MS的背景下，免疫调节设备的理解但基本特征。我们的 最近的研究表明，CD4-CD8效应器调节器动力学的几个新方面，并基于 这些发现，我们假设来自MS患者的CD4 T细胞具有内在增强的趋势 在炎症环境下发展效应子对免疫抑制的抗性，而MS的CD8 T细胞 患者具有内在增强的抑制能力较低的趋势。我们也假设 这些表型是塑料的，可以通过适当的刺激来调节。为了解决这些假设， 我们将采用两种约束的方法：（1）我们将解决MS中CD4抗性的生物学和调节 在自身免疫性疾病的背景下，直接了解这些过程。这个目标的一部分也将 正如我们最近的出版物所证明的那样，专注于IL-17细胞因子的新型CD4-Intrinsic生物学； （2） 我们还将解决MS中CD8抑制的生物学和调节。这些研究将提供 对基于MS发病机理的免疫失调的重要见解，对 MS和其他多种疾病环境中的治疗方法。