Kant Ravi, Pasi Shweta, Surolia Avadhesha
Molecular Science Laboratory, National Institute of Immunology, New Delhi-110067, India.
Sci Rep. 2015 Feb 3;5:8205. doi: 10.1038/srep08205.
MBP(85-99), an immuno-dominant epitope of myelin basic protein which binds to the major histocompatibility complex haplotype HLA-DR2 is widely implicated in the pathogenesis of multiple sclerosis. J5, an antagonist of MBP(85-99), that blocks the binding of MBP(85-99) to soluble HLA-DR2b much more efficiently than glatiramer acetate (a random copolymer comprising major MHC and T-cell receptor contact residues), was transformed into analogs with superior biological half-lives and antagonistic-activities by substitution of some of its residues with homo-β-amino acids. S18, the best analog obtained ameliorated symptoms of experimental autoimmune encephalomyelitis at least twice more effectively than glatiramer acetate or J5. S18 displayed marked resistance to proteolysis in-vitro; biological impact of which was evident in the form of delayed clinical onset of disease and prolonged therapeutic-benefits. Besides active suppression of MBP(85-99)-reactive CD4(+) T-cells in-vitro and in-vivo S18 treatment also generated IL-4 producing CD4(+) T-cell clones, through which protective effect could be transferred passively.
髓鞘碱性蛋白（85-99）是髓鞘碱性蛋白的一个免疫显性表位，可与主要组织相容性复合体单倍型HLA-DR2结合，在多发性硬化症的发病机制中广泛涉及。J5是MBP（85-99）的拮抗剂，它比醋酸格拉替雷（一种包含主要MHC和T细胞受体接触残基的随机共聚物）更有效地阻断MBP（85-99）与可溶性HLA-DR2b的结合，通过用同型β-氨基酸取代其一些残基，将其转化为具有更长生物半衰期和拮抗活性的类似物。获得的最佳类似物S18改善实验性自身免疫性脑脊髓炎症状的效果至少比醋酸格拉替雷或J5有效两倍。S18在体外显示出对蛋白水解的显著抗性；其生物学影响在疾病临床发病延迟和治疗益处延长的形式中明显可见。除了在体外和体内对MBP（85-99）反应性CD4(+) T细胞的活性抑制外，S18治疗还产生了产生IL-4的CD4(+) T细胞克隆，通过这些克隆可以被动转移保护作用。
