Kanwar J R, Harrison J E, Wang D, Leung E, Mueller W, Wagner N, Krissansen G W
Department of Molecular Medicine, School of Medicine and Health Science, University of Auckland, New Zealand.
J Neuroimmunol. 2000 Mar 1;103(2):146-52. doi: 10.1016/s0165-5728(99)00245-3.
A role for alpha4 integrins in different forms of the multiple sclerosis-like disease experimental autoimmune encephalomyelitis (EAE) has been demonstrated, but the individual contributions of alpha4beta1, alpha4beta7, and the related alphaEbeta7 integrin have not been determined. The P7 integrins alpha4beta7 and alphaEbeta7 play a central role in chronic inflammation, mediating the trafficking, entry, and/or adhesion of lymphocytes in the inflamed pancreas and gut, and their ligands MAdCAM-1, VCAM-1 and E-cadherin are expressed on brain endothelial cells and/or on microvessels in the inflamed central nervous system. Here, we show that an antibody directed against the beta7 subunit greatly attenuates a non-remitting form of EAE, induced by adoptive transfer of myelin oligodendrocyte peptide (MOG35-55)-stimulated T cells. Combinational treatment with both anti-beta7 and alpha4 integrin subunit antibodies led to more rapid and complete remission than that obtained with anti-alpha4 antibody alone, potentially implicating a role for alphaEbeta7 in disease progression. Remission correlated with the down-regulation of the vascular addressins VCAM-1. MAdCAM-1, and ICAM-1 on cerebral blood vessels. Attenuated forms of disease were induced by adoptive transfer of either wild-type encephalitogenic T cells to beta7-deficient gene knockout mice, or of beta7-/-encephalitogenic T cells to wild-type recipients. The former finding indicates that beta7 + ve recruited cells contribute to disease progression. Thus alpha4beta1, alpha4beta7, and alphaEbeta7 integrins may all play a contributory role in the progression of chronic forms of demyelinating disease, and together with their ligands could represent potential targets for improved treatment of some forms of multiple sclerosis.
α4整合素在不同形式的多发性硬化样疾病实验性自身免疫性脑脊髓炎（EAE）中所起的作用已得到证实，但α4β1、α4β7及相关的αEβ7整合素各自的作用尚未明确。P7整合素α4β7和αEβ7在慢性炎症中起核心作用，介导淋巴细胞在炎症胰腺和肠道中的运输、进入及/或黏附，其配体黏膜地址素细胞黏附分子-1（MAdCAM-1）、血管细胞黏附分子-1（VCAM-1）和E-钙黏蛋白在脑内皮细胞和/或炎症中枢神经系统的微血管上表达。在此，我们表明一种针对β7亚基的抗体可显著减轻由髓鞘少突胶质细胞糖蛋白（MOG35-55）刺激的T细胞过继转移诱导的一种非缓解型EAE。抗β7和α4整合素亚基抗体联合治疗比单独使用抗α4抗体能导致更快速和完全的缓解，这可能暗示αEβ7在疾病进展中起作用。缓解与脑血管上血管地址素VCAM-1、MAdCAM-1和细胞间黏附分子-1（ICAM-1）的下调相关。将野生型致脑炎性T细胞过继转移至β7缺陷基因敲除小鼠，或将β7基因敲除的致脑炎性T细胞过继转移至野生型受体，均可诱导疾病的减轻形式。前一发现表明β7阳性募集细胞有助于疾病进展。因此，α4β1、α4β7和αEβ7整合素可能在慢性脱髓鞘疾病的进展中均起作用，并且与其配体一起可能代表改善某些形式多发性硬化治疗的潜在靶点。
