Wu Chuan, Ivars Fredrik, Anderson Per, Hallmann Rupert, Vestweber Dietmar, Nilsson Per, Robenek Horst, Tryggvason Karl, Song Jian, Korpos Eva, Loser Karin, Beissert Stefan, Georges-Labouesse Elisabeth, Sorokin Lydia M
Institute for Physiological Chemistry and Pathobiochemistry, Münster University, Germany.
Nat Med. 2009 May;15(5):519-27. doi: 10.1038/nm.1957. Epub 2009 Apr 26.
Specific inhibition of the entry of encephalitogenic T lymphocytes into the central nervous system in multiple sclerosis would provide a means of inhibiting disease without compromising innate immune responses. We show here that targeting lymphocyte interactions with endothelial basement membrane laminins provides such a possibility. In mouse experimental autoimmune encephalomyelitis, T lymphocyte extravasation correlates with sites expressing laminin alpha4 and small amounts of laminin alpha5. In mice lacking laminin alpha4, laminin alpha5 is ubiquitously expressed along the vascular tree, resulting in marked and selective reduction of T lymphocyte infiltration into the brain and reduced disease susceptibility and severity. Vessel phenotype and immune response were not affected in these mice. Rather, laminin alpha5 directly inhibited integrin alpha(6)beta(1)-mediated migration of T lymphocytes through laminin alpha4. The data indicate that T lymphocytes use mechanisms distinct from other immune cells to penetrate the endothelial basement membrane barrier, permitting specific targeting of this immune cell population.
特异性抑制致脑炎性T淋巴细胞进入多发性硬化症患者的中枢神经系统，将提供一种在不损害固有免疫反应的情况下抑制疾病的方法。我们在此表明，靶向淋巴细胞与内皮基底膜层粘连蛋白的相互作用提供了这样一种可能性。在小鼠实验性自身免疫性脑脊髓炎中，T淋巴细胞外渗与表达层粘连蛋白α4和少量层粘连蛋白α5的部位相关。在缺乏层粘连蛋白α4的小鼠中，层粘连蛋白α5沿血管树普遍表达，导致T淋巴细胞向脑内浸润明显且选择性减少，疾病易感性和严重程度降低。这些小鼠的血管表型和免疫反应未受影响。相反，层粘连蛋白α5直接抑制整合素α(6)β(1)介导的T淋巴细胞通过层粘连蛋白α4的迁移。数据表明，T淋巴细胞利用与其他免疫细胞不同的机制穿透内皮基底膜屏障，从而允许对这一免疫细胞群体进行特异性靶向。
