Stepanov A V, Belogurov A A, Mamedov A É, Melamed D, Smirnov I V, Kuzina E S, Genkin D D, Boĭko A N, Sharanova S N, Bacon A, Ponomarenko N A, Gabibov A G
Bioorg Khim. 2012 May-Jun;38(3):306-14. doi: 10.1134/s1068162012030144.
Multiple Sclerosis (MS) is a serve autoimmune neurodegenerative disease. Development of innovative approaches of MS treatment is of a high priority in the modern immunology and pharmacy. In the present study we showed high therapeutic efficiency of immunodominant peptides of myelin basic protein (MBP) incorporated into the monolayer mannosylated liposomes on the development of experimental autoimmune encephalomyelitis (EAE) in DA rats. MBP is a component ofoligodendrocytes' membrane, which form axonal sheath, and is one of the major autoantigens in MS. We analyzed binding pattern ofanti-MBP autoantibodies from MS patients using previously designed MBP epitope library. Utilizing the same approach we investigated pool of anti-MBP antibodies from SJL/J and C57/BL6 mice and DA rats with induced EAE. The most relevant rodent model to MS was EAE in DA rats according to the autoantibodies' binding pattern. We selected three immunodominant MBP fragments encapsulated in monolayer mannosylated liposomes for the following treatment of verified DA rodent model. MBP fragment 46-62 was the most effective in reducing of the first EAE attack, whereas MBP 124-139 and 147-160 inhibited development of pathology during remission stage. Simultaneous administration of these peptides in liposomes significantly decreased level of anti-MBP antibodies. Synergetic therapeutic effect of MBP fragments reduced integral disease score by inhibiting first EAE wave and subsequent remission, thus, our findings disclosure novel approaches for efficient treatment of Multiple Sclerosis.
多发性硬化症(MS)是一种严重的自身免疫性神经退行性疾病。开发创新的MS治疗方法是现代免疫学和药学的高度优先事项。在本研究中,我们展示了掺入单层甘露糖化脂质体中的髓鞘碱性蛋白(MBP)免疫显性肽对DA大鼠实验性自身免疫性脑脊髓炎(EAE)发展的高治疗效率。MBP是形成轴突鞘的少突胶质细胞膜的组成部分,并且是MS中的主要自身抗原之一。我们使用先前设计的MBP表位文库分析了MS患者抗MBP自身抗体的结合模式。利用相同的方法,我们研究了来自SJL/J和C57/BL6小鼠以及诱导EAE的DA大鼠的抗MBP抗体库。根据自身抗体的结合模式,与MS最相关的啮齿动物模型是DA大鼠中的EAE。我们选择了封装在单层甘露糖化脂质体中的三个免疫显性MBP片段用于后续对已验证的DA啮齿动物模型的治疗。MBP片段46 - 62在减少首次EAE发作方面最有效,而MBP 124 - 139和147 - 160在缓解期抑制病理发展。这些肽在脂质体中的同时给药显著降低了抗MBP抗体的水平。MBP片段的协同治疗效果通过抑制首次EAE波和随后的缓解降低了整体疾病评分,因此,我们的发现揭示了有效治疗多发性硬化症的新方法。