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Immunobiological studies of interferons in multiple sclerosis.

机译：干扰素在多发性硬化症中的免疫生物学研究。

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摘要

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system that causes disability to young adults. MS is a complex and heterogenous disease and its causes are not well understood. The hallmarks of MS are inflammation, demyelination, axonal degeneration and atrophy of the central nervous system. The disease is polygeneic and multifactorial and exhibits sexual dimorphism in its prevalence; women are 2–3 times more likely to be affected than men.; Cytokines are known to contribute to MS activity progression and several studies implicate the proinflammatory Th1 cytokines, interferon-γ (IFN-γ), interleukin-2 (IL-2) and tumor necrosis factor-α (TNF-α), as disease-promoting whereas the Type 1 interferons, interferon-β (IFN-β) and interferon-α, have protective effects. IFN-γ and IFN-β share several elements in their signaling pathways and have overlapping biological activities. However, the pharmacological effects of these two IFNs in MS patients are very different—administration of IFN-γ causes exacerbations of MS symptoms but IFN-β is an approved drug for the treatment of MS that slows the progression to disability. The mechanism/s of IFN-β action are not well understood but several lines of evidence suggest that it acts as an immune-modifying agent on T-cells.; Flow cytometric approaches were used to study the secretion of IFN-γ, IL-2 and TNF-α from the peripheral blood-derived T cells of multiple sclerosis patients and healthy controls. The levels of TNF-α were correlated with the levels of IL-2 and IFN-γ in MS patients. This suggests that cytokine interactions rather than cytokine levels may play an important role in the disease. The differences in the cytokines secretion between male and female MS patients were also examined. Males had a higher percentage of TNF-α-secreting T cells and in females, disability measured on the Extended Disability Status Scale was correlated with the percentage of IFN-γ-secreting T cells.; DNA arrays containing over 4000 named human genes were used to delineate the effects of disease and IFN-β treatment on the peripheral blood cells of MS patients. The disease and treatment effects were restricted to a limited number of mRNAs; the levels of the majority of mRNAs were unaffected by treatment and the overall distribution patterns of mRNA levels were not altered. A total of 49 genes were found significantly different between MS patients and controls and several of these have not previously been associated with the MS disease state. IFN-β treatment significantly altered expression of 649 genes after 24 hours and significant increases in several benchmark mRNAs, β 2 microglobulin, signal transducer and activator of transcription-1, 1-8D, 1-8U, that are known to be induced by IFN-β were observed. Significant changes in the mRNA levels for various cytokines, cytokine receptors, adhesion molecules, antigen presentation and costimulation molecules were detected upon treatment. In addition, the DNA arrays were capable of detecting the mRNAs of several cytochrome P-450 and Phase 2 drug metabolizing enzymes and transporters in peripheral blood samples.; Thus, DNA array techniques have the potential to provide mRNA signatures that discriminate between various forms of MS and to provide metrics for assessing the responsiveness to IFN-β treatment in patients. The approach can also be extended to other disease-modifying MS therapies and eventually used for optimizing and individualizing drug dosing regimens.
机译：多发性硬化症（MS）是中枢神经系统的一种自身免疫性疾病，会导致年轻人残疾。 MS是一种复杂的异质性疾病，其病因尚不清楚。 MS的标志是炎症，脱髓鞘，轴突变性和中枢神经系统萎缩。该病是多基因和多因素的，在患病率中表现出性二态性。女性患病的可能性是男性的2-3倍。已知细胞因子可促进MS活性的发展，多项研究表明促炎性Th1细胞因子，干扰素-γ（IFN-γ），白细胞介素2（IL-2）和肿瘤坏死因子-α（TNF-α）是疾病-促进，而1型干扰素-干扰素-β（IFN-β）和干扰素-α具有保护作用。 IFN-γ和IFN-β在其信号通路中共享多个元素，并且具有重叠的生物学活性。但是，这两种IFN在MS患者中的药理作用是非常不同的-IFN-γ的使用会加重MS症状，但是IFN-β是用于MS的已获批准的药物，可减缓残疾的进展。 IFN-β作用的机制尚不清楚，但是有几条证据表明它可作为T细胞的免疫调节剂。流式细胞仪用于研究多发性硬化症患者和健康对照者外周血源性T细胞中IFN-γ，IL-2和TNF-α的分泌。 MS患者的TNF-α水平与IL-2和IFN-γ水平相关。这表明细胞因子相互作用而不是细胞因子水平可能在疾病中起重要作用。还检查了男性和女性MS患者之间细胞因子分泌的差异。男性的TNF-α分泌T细胞百分比更高，而女性的扩展残疾状况量表上测得的残疾与IFN-γ分泌T细胞的百分比相关。 DNA阵列包含4000多种命名的人类基因，用于描述疾病和IFN-β治疗对MS患者外周血细胞的影响。该疾病和治疗效果仅限于有限数量的mRNA。大多数mRNA的水平不受治疗的影响，mRNA水平的总体分布模式没有改变。发现总共49个基因在MS患者和对照组之间存在显着差异，其中一些以前与MS疾病状态无关。 IFN-β处理在24小时后显着改变了649个基因的表达，并显着增加了一些基准mRNA，β 2 微球蛋白，信号转导子和转录激活因子1、1-8D，1-8U，从而已知被IFN-β诱导。治疗后检测到各种细胞因子，细胞因子受体，粘附分子，抗原呈递和共刺激分子的mRNA水平发生了显着变化。此外，DNA阵列能够检测外周血样品中几种细胞色素P-450和2期药物代谢酶和转运蛋白的mRNA。因此，DNA阵列技术具有提供可区分各种形式的MS的mRNA标记和提供评估患者对IFN-β治疗反应性的指标的潜力。该方法还可以扩展到其他可改变疾病的MS疗法，并最终用于优化和个性化药物给药方案。

著录项

  • 作者

    Nguyen, Linh Thuy.;

  • 作者单位

    State University of New York at Buffalo.;

  • 授予单位 State University of New York at Buffalo.;
  • 学科 Biology Neuroscience.; Health Sciences Immunology.; Health Sciences Pharmacology.
  • 学位 Ph.D.
  • 年度 2001
  • 页码 300 p.
  • 总页数 300
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 神经科学;预防医学、卫生学;药理学;
  • 关键词

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