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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：
9382726
负责人：
STEPHEN D MILLER
金额：
$ 44.02万
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/9382726
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 Lymphoid 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 Organ 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 functional loss insight killings macrophage mature animal mouse model multiple sclerosis patient myelin degeneration nervous system disorder novel 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