Regulation of CD4+ T cell-mediated Demyelination Following Oligo Ablation

寡核苷酸消融后 CD4 T 细胞介导的脱髓鞘的调节

基本信息

批准号：
10198045
负责人：
STEPHEN D MILLER
金额：
$ 41.76万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-15 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10198045
关键词：
Ablation Acute Address Adoptive Transfer Adult Affect Animal Disease Models Animals Antigen-Presenting Cells Antigens Autoimmune Diseases Autoimmune Responses Autoimmunity Automobile Driving Axon Blood - brain barrier anatomy Brain CD4 Positive T Lymphocytes Cells Cessation of life Chronic Chronic Progressive Multiple Sclerosis Clinical Defect Demyelinating Diseases Demyelinations Deterioration Development Diphtheria Toxin Disease Effector Cell Epidemiology Etiology Event FOXP3 gene Frequencies Functional disorder Gender Genetic ITGAM gene Immune Immune Tolerance Immune system Immunologic Adjuvants Incidence Individual Infiltration Inflammation Inflammatory Kinetics Late-Onset Disorder Lead Lesion Life Mediating Microglia Modeling Multiple Sclerosis Multiple Sclerosis Lesions Mus Myelin Myelin Sheath Neuraxis Neurodegenerative Disorders Neurologic Neurologic Deficit Neurologic Symptoms Neuronal Dysfunction Oligodendroglia Oligonucleotides Onset of illness Pathogenesis Pathogenicity Pathologic Peptides Peripheral Phase Phenotype Play Population Progressive Disease Publishing Recovery Recurrence Regulation Regulatory T-Lymphocyte Relapse Reporter Role Severity of illness Symptoms T cell response T-Lymphocyte Tamoxifen Testing Time Tissues Transgenic Organisms Work adaptive immune response alpha Toxin autoreactive T cell autoreactivity axon injury base design effector T cell functional loss insight macrophage mature animal mouse model multiple sclerosis patient myelin degeneration nervous system disorder novel peripheral lymphoid organ preservation promoter remyelination response theories white matter young adult

项目摘要

Although multiple sclerosis (MS) is the most common neurological disorder to afflict young adults, much remains unknown with regard to the etiology and pathogenesis of this disease. Epidemiologic evidence indicates that there are environmental, gender and genetic factors that influence disease incidence. Nevertheless, the triggering event that initiates the autoimmune response against the myelin sheath is unclear. MS usually begins as a remitting/relapsing inflammatory demyelinating disorder, but in most individuals the disease progresses to a chronic neurological condition that correlates with the accumulation of axonal damage. To further our understanding of this disorder, we have developed a new mouse model of inducible, widespread oligodendrocyte ablation by inducing expression of diptheria toxin A under control of the PLP promoter that results in extensive CNS demyelination in adult animals (DTA model). Strikingly, these animals display robust CNS remyelination that correlates with the recovery from the severe neurological symptoms that the mice display at the peak of disease. At the peak of the early disease course the blood brain barrier remains intact, T cells are not detected within the CNS and axons are preserved. Despite the robust early recovery that these animals display in response to oligodendrocyte (ODC) ablation, within 6 months they succumb to a severe inflammatory neurological condition supporting the `inside-out' model of MS pathogenesis. This late phase progressive disease is characterized by CNS accumulation of myelin-specific CD4+ T cells and widespread focal demyelination. We propose to utilize the DTA model to study fundamental aspects of adult-onset remyelination and demyelination. We will test the hypothesis that the initial CD4+ T cell response to ODC ablation is protective/regulatory, but eventual loss of myelin peptide-specific tolerance/regulation leads to the induction of CD4+ T cell-mediated late-onset disease. We will explore the role that both innate and adaptive immune responses play in development of chronic inflammatory demyelination. While our previously published work shows that there is an increase in the number and activation of CD11b+ cells in the CNS following initial ODC ablation, the question remains whether microglia or peripheral macrophages/DCs are the predominant antigen presenting cells that activate the later influx of pathogenic CD4+ T cells. We will also determine, similar to MS pathogenesis, why there is a lengthy lag time between the initial ODC ablation and the late-onset CD4+ T cell-mediated chronic demyelinating phase. To define the immune mechanisms underlying the transition to late-onset T cell-mediated demyelination, we will exploit strategies to increase the frequency and infiltration of myelin-specific effector and regulatory T cells into the CNS of the DTA mice during the initial disease phase. We will also elucidate the underlying immunopathologic T cell mechanism(s) driving late-onset immune- mediated demyelination. These studies will examine the exciting possibility that the initial ODC loss and demyelination trigger autoreactive myelin-specific T cell responses in a model of chronic progressive MS.

尽管多发性硬化症 (MS) 是困扰年轻人的最常见的神经系统疾病，但关于这种疾病的病因和发病机制仍不清楚。流行病学证据表明环境、性别和遗传因素会影响疾病的发生。然而，引发针对髓鞘的自身免疫反应的触发事件尚不清楚。 MS 通常以缓解/复发性炎性脱髓鞘疾病开始，但在大多数个体中疾病进展为慢性神经系统疾病，与轴突损伤的积累相关。为了进一步了解这种疾病，我们开发了一种新的可诱导的、广泛的小鼠模型通过在 PLP 启动子的控制下诱导白喉毒素 A 的表达来消除少突胶质细胞导致成年动物广泛的中枢神经系统脱髓鞘（DTA 模型）。引人注目的是，这些动物表现出强大的中枢神经系统髓鞘再生与小鼠严重神经系统症状的恢复相关表现在疾病高峰期。在早期病程的高峰期，血脑屏障保持完整，T 中枢神经系统内未检测到细胞，轴突得以保留。尽管早期复苏强劲，但这些动物对少突胶质细胞 (ODC) 消融做出反应，在 6 个月内死于严重的炎症性神经系统疾病支持多发性硬化症发病机制的“由内而外”模型。这个后期阶段进行性疾病的特点是中枢神经系统中髓磷脂特异性 CD4+ T 细胞的积累，并且广泛存在局灶性脱髓鞘。我们建议利用 DTA 模型来研究成人发病的基本方面髓鞘再生和脱髓鞘。我们将检验以下假设：CD4+ T 细胞对 ODC 的初始反应消融是保护性/调节性的，但最终髓磷脂肽特异性耐受/调节的丧失会导致诱导 CD4+ T 细胞介导的迟发性疾病。我们将探讨先天性和适应性的作用免疫反应在慢性炎症脱髓鞘的发展中发挥作用。虽然我们之前发布的研究表明，在初始治疗后，中枢神经系统中 CD11b+ 细胞的数量和活化有所增加 ODC 消融，问题仍然是小胶质细胞还是外周巨噬细胞/DC 是主要的激活随后流入的致病性 CD4+ T 细胞的抗原呈递细胞。我们还将确定，类似对于 MS 发病机制，为什么初始 ODC 消融和迟发 CD4+ 之间存在较长的滞后时间 T细胞介导的慢性脱髓鞘阶段。定义转变背后的免疫机制晚发性 T 细胞介导的脱髓鞘，我们将利用策略来增加脱髓鞘的频率和浸润在疾病初始阶段，髓磷脂特异性效应细胞和调节性 T 细胞进入 DTA 小鼠的中枢神经系统。我们还将阐明驱动迟发性免疫的潜在免疫病理学 T 细胞机制介导的脱髓鞘。这些研究将检验最初的 ODC 损失和在慢性进行性多发性硬化症模型中，脱髓鞘会触发自身反应性髓磷脂特异性 T 细胞反应。