Tissue plasminogen activator (tPA), a component of the plasminogen activator (PA) system, is elevated in inflammatory neurological disorders. In the present study, we explored the immunomodulatory activity of tPA in experimental autoimmune encephalomyelitis (EAE). The EAE was treated with two catalytic inactive tPA variant proteins: S(481)A and S(481)A + KHRR(296-299)AAAA. EAE-induced tPA-/- mice presented with markedly more severe disease than wt EAE mice. Further, treatment with tPA variants, demonstrated a significant suppression of disease severity in tPA-/- and wt mice. Immunological evaluation showed that specific T-cell reactivity was markedly reduced in the tPA-/- animals, as indicated by decreased T-cell reactivity and reduction in T-regulatory cells. The current findings indicate that tPA plays a role in the pathogenesis of EAE. Moreover, successful amelioration of EAE was achieved by administration of tPA variant proteins. This might mean that these proteins have potential for the immunomodulation of neuroinflammation.

中文翻译：

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组织纤溶酶原激活物在实验性自身免疫性脑脊髓炎临床加重中的作用及其治疗潜力。

组织纤溶酶原激活物（tPA）是纤溶酶原激活物（PA）系统的组成部分，在炎症性神经系统疾病中升高。在本研究中，我们探讨了tPA在实验性自身免疫性脑脊髓炎（EAE）中的免疫调节活性。用两种催化的非活性tPA变异蛋白处理EAE：S（481）A和S（481）A + KHRR（296-299）AAAA。与wt EAE小鼠相比，EAE诱导的tPA-/-小鼠表现出更为严重的疾病。进一步地，用tPA变体治疗证明了在tPA-/-和wt小鼠中疾病严重性的显着抑制。免疫学评估表明，tPA-/-动物体内的特异性T细胞反应性显着降低，这表现为T细胞反应性降低和T调节细胞减少。当前的发现表明tPA在EAE的发病机理中起作用。此外，通过施用tPA变体蛋白成功改善了EAE。这可能意味着这些蛋白质具有免疫调节神经炎症的潜能。