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

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，但许多 关于这种疾病的病因和发病机制，目前尚不清楚。流行病学证据 表明有环境、性别和遗传因素影响疾病发病率。 然而，启动针对髓鞘的自身免疫反应的触发事件尚不清楚。 MS通常以缓解性/复发性炎性脱髓鞘障碍开始，但在大多数人中 疾病发展为一种与轴突损伤积累相关的慢性神经疾病。 为了进一步了解这种疾病，我们开发了一种新的可诱导、广泛传播的小鼠模型。 在PLP启动子的控制下通过诱导白喉毒素A的表达来消融少突胶质细胞 导致成年动物广泛的中枢神经系统脱髓鞘(DTA模型)。令人惊讶的是，这些动物表现得很健壮 中枢神经系统再髓鞘形成与小鼠严重神经症状的恢复相关 在疾病高峰期表现出来。在早期病程的高峰期，血脑屏障保持完好，T 中枢神经系统内没有检测到细胞，轴突被保留下来。尽管强劲的早期复苏，但这些 动物表现出对少突胶质细胞(ODC)消融的反应，在6个月内它们会死于严重的 炎性神经状态支持MS发病的“内向外”模型。这个后期阶段 进展性疾病的特点是中枢神经系统髓鞘特异性CD4T细胞的积聚和广泛的 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。 重新髓鞘形成和脱髓鞘。我们将检验这样一种假设，即初始的CD4T细胞对ODC的反应 消融是保护性/调节性的，但最终失去髓鞘多肽特异性的耐受性/调节性导致 CD4T细胞介导的迟发性疾病的诱导。我们将探索先天和后天的角色 免疫反应在慢性炎性脱髓鞘的发生发展中起作用。虽然我们之前发表的 研究表明，在中枢神经系统中，CD11b细胞的数量和激活在最初的 ODC消融，问题仍然是小胶质细胞还是外周巨噬细胞/DC占主导地位 抗原提呈细胞，激活稍后涌入的致病的CD4T细胞。我们还将确定，类似的 对于MS的发病机制，为什么在最初的ODC消融和迟发的CD4之间有很长的滞后时间 T细胞介导的慢性脱髓鞘阶段。为了定义转变为 迟发性T细胞介导的脱髓鞘，我们将利用策略增加频率和渗透 在疾病初期，髓鞘特异性效应T细胞和调节性T细胞进入DTA小鼠的中枢神经系统。 我们还将阐明晚发型免疫的潜在免疫病理T细胞机制(S)。 介导性脱髓鞘。这些研究将检验令人兴奋的可能性，即最初的ODC损失和 脱髓鞘在慢性进行性多发性硬化模型中触发自身反应性髓鞘特异性T细胞反应

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.