IMMUNOLOGICAL FACTORS IN NARCOLEPSY

发作性睡病的免疫因素

基本信息

批准号：
6539560
负责人：
JEROME M SIEGEL
金额：
$ 35.87万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
1983
资助国家：
美国
起止时间：
1983-02-01 至 2003-06-30
项目状态：
已结题

项目摘要

Description (Applicant's Abstract): Narcolepsy is characterized by overwhelming sleepiness, cataplexy, sleep paralysis and hypnagogic hallucinations. Genetic studies have identified a link between narcolepsy and HLA haplotype. Because the HLA region specifies the proteins used to present antigen and because most HLA linked diseases are autoimmune, it has been suggested that narcolepsy is an autoimmune disease. However, there is no convincing evidence for this hypothesis. During the current grant period we have found the first evidence for a neurodegenerative process in narcolepsy. Studying narcoleptic dogs, we saw that degeneration occurred over a relatively short time period and was localized to basal forebrain, amygdala and adjacent regions. These regions are known to have key roles in the control of sleep and in the regulation of brainstem motor tone control systems. The highly localized nature of the degeneration and the relatively short duration of the degenerative events may explain the failure to find evidence for active immune processes in fully symptomatic human or canine narcoleptics. We conducted a pilot study of the effects of immunosuppression on narcoleptic dogs during the period of degeneration, using glucocorticoids, azathioprine and methotrexate. We saw a delay of symptom onset and a marked reduction of symptom intensity in all treated animals. The change in symptom severity appears to be permanent. We also found evidence that immune activation exacerbates symptomatology. If verified in a larger group of animals, these would be the first manipulations shown to affect the course of the narcoleptic disease process, and would be important evidence for immune system involvement in the pathogenesis of narcolepsy. In further pilot work, we saw CD3+ T cells at the sites of degeneration in untreated narcoleptics, key evidence for immune involvement. We propose to study the effect of immunosuppression on the development of narcolepsy. We will determine whether we can completely prevent the development of symptoms with combined prednisone and methotrexate treatment. We will see whether there is a critical period for intervention. We will determine whether immune activation exacerbates symptomatology. We will look for evidence of lymphocytes and activated microglia at the sites where we have seen degeneration. This work could lead to a treatment for human narcolepsy and to a better understanding of the cause of this debilitating disease.

描述（申请人摘要）：发作性睡病的特征是极度嗜睡、猝倒、睡眠麻痹和入睡前幻觉。遗传学研究已确定发作性睡病与 HLA 单倍型之间的联系。由于 HLA 区域指定了用于呈递抗原的蛋白质，并且大多数 HLA 相关疾病都是自身免疫性疾病，因此有人认为发作性睡病是一种自身免疫性疾病。然而，这一假设没有令人信服的证据。在当前的资助期内，我们发现了发作性睡病神经退行性过程的第一个证据。通过研究发作性睡病犬，我们发现退化发生在相对较短的时间内，并且局限于基底前脑、杏仁核和邻近区域。已知这些区域在睡眠控制和脑干运动音调控制系统的调节中发挥关键作用。退化的高度局部性和退化事件相对较短的持续时间可能解释了为何未能在完全有症状的人类或犬类嗜睡症患者中找到主动免疫过程的证据。我们使用糖皮质激素、硫唑嘌呤和甲氨蝶呤进行了一项初步研究，研究免疫抑制对发作性睡病犬在退化期间的影响。我们发现所有接受治疗的动物的症状出现延迟且症状强度显着降低。症状严重程度的变化似乎是永久性的。我们还发现证据表明免疫激活会加剧症状。如果在更大的动物群体中得到验证，这些将是第一个被证明可以影响发作性睡病病程的操作，并且将成为免疫系统参与发作性睡病发病机制的重要证据。在进一步的试点工作中，我们在未经治疗的发作性睡病患者的退化部位看到了 CD3+ T 细胞，这是免疫参与的关键证据。我们建议研究免疫抑制对发作性睡病发生的影响。我们将确定泼尼松和甲氨蝶呤联合治疗是否可以完全预防症状的发展。我们将观察是否存在干预的关键时期。我们将确定免疫激活是否会加剧症状。我们将在我们看到退化的部位寻找淋巴细胞和激活的小胶质细胞的证据。这项工作可能会导致人类嗜睡症的治疗，并更好地了解这种使人衰弱的疾病的原因。