Elliott E A, McFarland H I, Nye S H, Cofiell R, Wilson T M, Wilkins J A, Squinto S P, Matis L A, Mueller J P
Department of Immunobiology, Alexion Pharmaceuticals, Inc., New Haven, Connecticut 06511, USA.
J Clin Invest. 1996 Oct 1;98(7):1602-12. doi: 10.1172/JCI118954.
It has been shown that peripheral T cell tolerance can be induced by systemic antigen administration. We have been interested in using this phenomenon to develop antigen-specific immunotherapies for T cell-mediated autoimmune diseases. In patients with the demyelinating disease multiple sclerosis (MS), multiple potentially autoantigenic epitopes have been identified on the two major proteins of the myelin sheath, myelin basic protein (MBP) and proteolipid protein (PLP). To generate a tolerogenic protein for the therapy of patients with MS, we have produced a protein fusion between the 21.5-kD isoform of MBP (MBP21.5) and a genetically engineered form of PLP (deltaPLP4). In this report, we describe the effects of treatment with this agent (MP4) on clinical disease in a murine model of demyelinating disease, experimental autoimmune encephalomyelitis (EAE). Treatment of SJL/J mice with MP4 after induction of EAE either by active immunization or by adoptive transfer of activated T cells completely prevented subsequent clinical paralysis. Importantly, the administration of MP4 completely suppressed the development of EAE initiated by the cotransfer of both MBP- and PLP-activated T cells. Prevention of clinical disease after the intravenous injection of MP4 was paralleled by the formation of long-lived functional peptide-MHC complexes in vivo, as well as by a significant reduction in both MBP- and PLP-specific T cell proliferative responses. Mice treated with MP4 were resistant to disease when rechallenged with an encephalitogenic PLP peptide emulsified in CFA, indicating that MP4 administration had a prolonged effect in vivo. Administration of MP4 was also found to markedly ameliorate the course of established clinical disease. Finally, MP4 therapy was equally efficacious in mice defective in Fas expression. These results support the conclusion that MP4 protein is highly effective in suppressing disease caused by multiple neuroantigen epitopes in experimentally induced demyelinating disease.
已表明全身给予抗原可诱导外周T细胞耐受。我们一直致力于利用这一现象开发针对T细胞介导的自身免疫性疾病的抗原特异性免疫疗法。在患有脱髓鞘疾病多发性硬化症（MS）的患者中，已在髓鞘的两种主要蛋白质髓鞘碱性蛋白（MBP）和蛋白脂蛋白（PLP）上鉴定出多个潜在的自身抗原表位。为了产生用于治疗MS患者的致耐受性蛋白，我们制备了MBP的21.5-kD异构体（MBP21.5）与基因工程形式的PLP（deltaPLP4）之间的蛋白融合体。在本报告中，我们描述了用该制剂（MP4）治疗脱髓鞘疾病实验性自身免疫性脑脊髓炎（EAE）小鼠模型中的临床疾病的效果。在通过主动免疫或活化T细胞的过继转移诱导EAE后，用MP4治疗SJL/J小鼠可完全预防随后的临床瘫痪。重要的是，给予MP4可完全抑制由MBP和PLP活化的T细胞共转移引发的EAE的发展。静脉注射MP4后预防临床疾病与体内形成长寿的功能性肽-MHC复合物以及MBP和PLP特异性T细胞增殖反应的显著降低平行。用MP4治疗的小鼠在用CFA乳化的致脑炎性PLP肽再次攻击时对疾病具有抗性，表明给予MP4在体内具有延长的作用。还发现给予MP4可明显改善已确立的临床疾病的病程。最后，MP4疗法在Fas表达缺陷的小鼠中同样有效。这些结果支持以下结论：MP4蛋白在抑制实验性诱导的脱髓鞘疾病中由多种神经抗原表位引起的疾病方面非常有效。
