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

虽然多发性硬化症（MS）是最常见的神经系统疾病折磨年轻人， 关于这种疾病的病因和发病机制仍然未知。流行病学证据 表明有环境，性别和遗传因素影响疾病的发病率。 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， 疾病进展为与轴突损伤累积相关的慢性神经病症。 为了进一步了解这种疾病，我们开发了一种新的小鼠模型， 通过在PLP启动子控制下诱导白喉毒素A的表达来消除少突胶质细胞， 导致成年动物中广泛的CNS脱髓鞘（DTA模型）。引人注目的是，这些动物 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， 在疾病的高峰期出现。在早期病程的高峰期，血脑屏障保持完整，T 在CNS内未检测到细胞，轴突得以保留。尽管强劲的早期复苏， 动物显示对少突胶质细胞（ODC）消融的反应，在6个月内，它们死于严重的 炎性神经病症支持MS发病机制的“由内而外”模型。这个晚期阶段 进行性疾病的特征在于髓鞘特异性CD 4 + T细胞的CNS积累和广泛的 局部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。我们将检验一个假设，即最初的CD 4 + T细胞对ODC的应答 消融是保护性/调节性的，但髓鞘肽特异性耐受性/调节的最终丧失导致 诱导CD 4 + T细胞介导的迟发性疾病。我们将探讨先天的和适应性的 免疫反应在慢性炎性脱髓鞘形成中起作用。虽然我们之前发布的 研究表明，在最初的免疫后，CNS中CD 11b+细胞的数量和活化增加， ODC消融后，问题仍然是小胶质细胞或外周巨噬细胞/DC是否占主导地位。 抗原呈递细胞，其激活致病性CD 4 + T细胞的后期流入。我们还将确定，类似 MS发病机制，为什么在最初的ODC消融和迟发性CD 4+之间有很长的滞后时间， T细胞介导的慢性脱髓鞘阶段。为了确定免疫机制的基础过渡到 迟发性T细胞介导的脱髓鞘，我们将利用策略，以增加频率和浸润， 髓鞘特异性效应和调节性T细胞进入DTA小鼠的CNS。 我们还将阐明潜在的免疫病理T细胞机制（S）驱动晚发型免疫- 介导的脱髓鞘。这些研究将检验最初的ODC损失和 脱髓鞘在慢性进行性MS模型中触发自身反应性髓鞘特异性T细胞应答

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.