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）是折磨年轻人的最常见神经系统疾病，但关于该疾病的病因和发病机理，仍然未知。流行病学证据表明存在影响疾病发病率的环境，性别和遗传因素。然而，启动对髓鞘鞘的自身免疫反应的触发事件尚不清楚。 MS通常是作为一种恢复/复发性的炎症性脱髓鞘障碍，但在大多数个体中疾病发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诱导，广泛的鼠标模型通过诱导PLP启动子控制的白喉毒素A的表达来诱导少突胶质细胞消融导致成年动物中CNS脱髓鞘广泛（DTA模型）。令人惊讶的是，这些动物表现强大中枢神经系统再递送与小鼠的严重神经系统症状的恢复相关显示在疾病的顶峰。在早期疾病病程的顶峰上，血脑屏障保持完整，t 在中枢神经系统中未检测到细胞，并保留轴突。尽管早期恢复了强大的恢复动物响应少突胶质细胞（ODC）消融，在6个月内屈服于严重支持MS发病机理的“内而外”模型的炎性神经系统状况。这个后期进行性疾病的特征是中枢神经系统的髓磷脂特异性CD4+ T细胞的积累和广泛的特征局灶性脱髓鞘。我们建议利用DTA模型来研究成人发行的基本方面再髓和脱髓鞘。我们将测试初始CD4+ T细胞对ODC的响应的假设消融是保护/调节性的，但最终损失髓磷脂肽特异性耐受性/调节导致诱导CD4+ T细胞介导的晚期疾病。我们将探讨先天和适应性的角色免疫反应在慢性炎症性脱髓鞘发展方面发挥了作用。虽然我们以前出版工作表明，初始CNS中CD11b+细胞的数量和激活有所增加 ODC消融，问题仍然是小胶质细胞或外围巨噬细胞/DC是主要的抗原呈现细胞，可激活后来的致病CD4+ T细胞的流入。我们还将确定类似的对于MS发病机理，为什么在初始ODC消融和晚期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。定义过渡到过渡的背后的免疫机制晚发t细胞介导的脱髓鞘，我们将利用策略来增加频率和渗透在初始疾病阶段，髓磷脂特异性效应子和调节性T细胞进入DTA小鼠的中枢神经中心。我们还将阐明驱动晚期免疫的潜在免疫病理T细胞机制介导的脱髓鞘。这些研究将研究最初的ODC损失和脱髓鞘触发自动反应性髓磷脂特异性T细胞反应在慢性进行性MS模型中。