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多发性硬化症患者的疾病相关抗原反应性T细胞系与IV型胶原的相互作用:整合素VLA-1的作用及辐射效应

Interaction of disease-related antigen-reactive T-cell lines from multiple sclerosis patients with type IV collagen: role of integrin VLA-1 and effects of irradiation.

作者信息

Bank Ilan, Achiron Anat, Levie Gad, Koltakov Alexander, Mandel Mathilda

机构信息

Department of Medicine F, Sheba Medical Center and Tel Aviv University, Tel Hashomer, Israel.

出版信息

J Clin Immunol. 2002 May;22(3):153-63. doi: 10.1023/a:1015472013500.

Abstract

Multiple sclerosis (MS), a chronic demyelinating disease, is thought to be initiated by pathogenic T cells that transmigrate the vascular endothelium and enter the brain through vascular and parenchymal basement membranes (BM). Vaccination with T-cell lines reactive with myelin basic protein (MBP) and myelin oligodendrocytic glycoprotein (MOG) epitopes, expanded with interleukin-2 (IL-2), and attenuated by ionizing radiation is currently being evaluated as a therapeutic modality for this disease. We examined mechanisms potentially involved in pathogenic cell migration into the central nervous system (CNS) and the influence of irradiation on these processes. Seven of 7 autoantigen-responsive T-cell lines from MS patients adhered to collagen IV, the major collagenous constituent of BMs. This adhesion was inhibited almost completely by monoclonal antibody (MAb) to very late antigen (VLA)-1 and partially by anti-VLA-2. T-cell lines from healthy donors adhered more variably to collagen IV. Furthermore, patient derived T cells actively transmigrated through a collagen IV gel toward medium containing TNF-a, in a process that was inhibited by MAbs to VLA-1. Ionizing radiation at the dose used in vaccine preparation, inhibited morphological polarization associated with migratory capability, induced integrin clustering on the cell membrane, and abrogated adhesion to collagen IV. These findings may have important implications for understanding the pathogenesis of MS and how irradiation of potentially pathogenic T cells produces a reagent with possible therapeutic effects in T-cell vaccination (TCV).

摘要

多发性硬化症(MS)是一种慢性脱髓鞘疾病,被认为是由致病性T细胞引发的,这些T细胞穿过血管内皮,通过血管和实质基底膜(BM)进入大脑。用与髓鞘碱性蛋白(MBP)和髓鞘少突胶质细胞糖蛋白(MOG)表位反应的T细胞系进行疫苗接种,该T细胞系用白细胞介素-2(IL-2)扩增并用电离辐射减毒,目前正在作为这种疾病的一种治疗方式进行评估。我们研究了致病性细胞迁移到中枢神经系统(CNS)中可能涉及的机制以及辐射对这些过程的影响。来自MS患者的7个自身抗原反应性T细胞系中有7个黏附于基底膜的主要胶原成分IV型胶原。这种黏附几乎完全被抗极迟抗原(VLA)-1单克隆抗体(MAb)抑制,部分被抗VLA-2抑制。来自健康供体的T细胞系对IV型胶原的黏附情况变化较大。此外,患者来源的T细胞在一个被抗VLA-1单克隆抗体抑制的过程中,通过IV型胶原凝胶向含有肿瘤坏死因子-α(TNF-α)的培养基中主动迁移。疫苗制备中使用的剂量的电离辐射抑制了与迁移能力相关的形态极化,诱导了细胞膜上整合素的聚集,并消除了对IV型胶原的黏附。这些发现可能对理解MS的发病机制以及潜在致病性T细胞的辐射如何在T细胞疫苗接种(TCV)中产生具有可能治疗作用的试剂具有重要意义。

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