The role of the very late antigen-4 and its counterligand vascular cell adhesion molecule-1 in the pathogenesis of experimental autoimmune neuritis of the Lewis rat
The role of the very late antigen-4 and its counterligand vascular cell adhesion molecule-1 in the pathogenesis of experimental autoimmune neuritis of the Lewis rat
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DOI：
10.1093/brain/121.7.1257
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发表时间：
1998-07-01
期刊：
影响因子：
14.5
通讯作者：
Gold, R
中科院分区：
文献类型：
--
作者：
Enders, U;Lobb, R;Gold, R
我们使用中和单克隆抗体 (mAb) 作为探针，研究了极晚期抗原 4 [VLA-4（α 4/β 1）整联蛋白] 和血管细胞粘附分子 1 (VCAM-1) 在实验性自身免疫性神经炎 (EAN)（吉兰-巴利综合征的动物模型）中的功能作用。通过静脉内过继转移 P-2 特异性 T 细胞 (AT-EAN) 或通过牛髓磷脂 (活性 EAN) 免疫诱导疾病。细胞转移前 4 小时和第 3 天，在 AT-EAN 中使用 500 μg 抗 VLA-4 mAb (TA-2) 或同种型对照抗体进行预防性治疗。在疾病诱导前 4 小时以及第 2、4 和 6 天，在 AT-EAN 中静脉注射 500 μg 抗 VCAM-1 mAb (5F10) 或相应的同种型对照抗体。在第 5、9 和 13 天进行针对 VLA-4 或 VCAM-1 的单克隆抗体。免疫组织化学检查发现，坐骨神经中的 VCAM-1 在 EAN 早期（T 细胞移植后第 3-5 天）上调，而在健康对照中未发现表达。在两种 EAN 模型中，VLA-4 的阻断显着减轻了疾病的严重程度。 VCAM-1 的阻断也显着改善了病程并减少了坐骨神经中的 T 细胞浸润，但程度较轻。这些实验证明了 VLA-4 在 EAN 发病机制中的关键作用，并表明 VCAM-1 表达的上调至少部分地促进了疾病的早期进展。未来的研究需要评估其他 VLA-4 配体的潜在贡献。
We have investigated the functional role of very late antigen-4 [VLA-4 (alpha 4/beta 1) integrin] and vascular cell adhesion molecule-1 (VCAM-1) in experimental autoimmune neuritis (EAN), an animal model of the Guillain-Barre syndrome, using neutralizing monoclonal antibodies (mAbs) as probes. Disease was induced by intravenous adoptive transfer of P-2 specific T cells (AT-EAN), or by immunization with bovine myelin (active EAN). Preventive treatment with 500 mu g anti-VLA-4 mAb (TA-2) or with an isotype control antibody was given in AT-EAN 4h before cell transfer and at day 3. Intravenous injection of 500 mu g anti-VCAM-1 mAb (5F10) or a corresponding isotype control was given in AT-EAN 4 h before disease induction, and at days 2, 4 and 6. Preventive treatment of active EAN with mAb to VLA-4 or VCAM-1 was performed at days 5, 9 and 13. On immunohistochemical examination, VCAM-1 in sciatic nerve was found to be upregulated at early stages of EAN (days 3-5 after T-cell transfer), whilst no expression was noted in healthy controls. In both EAN models, blockade of VLA-4 markedly attenuated disease severity. Blockade of VCAM-1 also significantly ameliorated the disease course and diminished T-cell infiltration in sciatic nerve, but to a lesser degree. These experiments demonstrate the critical role of VLA-4 in the pathogenesis of EAN and show that upregulation of VCAM-1 expression contributes, at least in part, to the progression of the disease in the early stages. Future studies are needed to assess the potential contribution of other VLA-4 ligands.