van der Meide P H, de Labie M C, Ruuls S R, Groenestein R J, Botman C A, Olsson T, Dijkstra C D
Department of Immunobiology, Biomedical Primate Research Centre, Rijswijk, The Netherlands.
J Neuroimmunol. 1998 Apr 1;84(1):14-23. doi: 10.1016/s0165-5728(97)00207-5.
IFN-beta has recently been shown to exert remarkable beneficial effects on disease development in patients with early stage relapsing-remitting MS. The specific immune mechanism(s) by which IFN-beta ameliorates this human demyelinating disease is at present undefined. One potential mechanism may reside in the antiproliferative activity of IFN-beta which may inhibit the expansion of autoaggressive T cells thereby limiting disease progression. In the present study we investigated whether the administration of recombinant rat IFN-beta (rrIFN-beta) to Lewis rats with actively induced experimental autoimmune encephalomyelitis (EAE) inhibits the expansion of encephalitogenic T cells in lymphoid organs and as such may contribute to suppression of disease activity in this widely used animal model for MS. Our data show that daily administrations of > or = 3 x 10(5) u rrIFN-beta to EAE rats, starting two days before MBP sensitization and continued for 10 days led to a dramatic and dose-dependent reduction in encephalitogenic T cells in both spleen and inguinal lymph nodes at day 8 post-immunization (p.i.). However, the rrIFN-beta-mediated reduction in effector T cells did not ameliorate paralytic disease as expected but significantly enhanced the severity of EAE. Analyses of lymphoid organs in the remission phase of EAE revealed strongly elevated numbers of encephalitogenic T cells in rrIFN-beta-treated versus control rats suggesting a rapid reversal of the antiproliferative action of rrIFN-beta followed by an overshoot in the subsequent expansion of these effector T cells. In conformity with higher numbers of encephalitogenic T cells and worsening of disease, animals also showed significantly greater perivascular inflammation in the CNS. The relevance of our findings in relation to the beneficial effects of IFN-beta in MS is discussed.
最近有研究表明，干扰素-β（IFN-β）对早期复发缓解型多发性硬化症（MS）患者的疾病发展具有显著的有益作用。目前尚不清楚IFN-β改善这种人类脱髓鞘疾病的具体免疫机制。一种潜在机制可能在于IFN-β的抗增殖活性，它可能抑制自身攻击性T细胞的扩增，从而限制疾病进展。在本研究中，我们调查了给主动诱导实验性自身免疫性脑脊髓炎（EAE）的Lewis大鼠注射重组大鼠IFN-β（rrIFN-β）是否会抑制淋巴器官中致脑炎性T细胞的扩增，进而有助于抑制这种广泛用于MS研究的动物模型中的疾病活动。我们的数据显示，在髓鞘碱性蛋白（MBP）致敏前两天开始，每天给EAE大鼠注射≥3×10⁵单位的rrIFN-β，并持续10天，在免疫后第8天，脾脏和腹股沟淋巴结中的致脑炎性T细胞数量出现了显著的剂量依赖性减少。然而，rrIFN-β介导的效应T细胞减少并未如预期改善麻痹性疾病，反而显著加重了EAE的严重程度。对EAE缓解期淋巴器官的分析显示，与对照大鼠相比，rrIFN-β处理的大鼠中致脑炎性T细胞数量大幅增加，这表明rrIFN-β的抗增殖作用迅速逆转，随后这些效应T细胞的扩增出现反弹。与致脑炎性T细胞数量增加和疾病恶化一致，动物中枢神经系统中的血管周围炎症也明显更严重。我们讨论了这些发现与IFN-β在MS中的有益作用的相关性。
