Novel synthetic amino acid copolymers that inhibit autoantigen-specific T cell responses and suppress experimental autoimmune encephalomyelitis
Novel synthetic amino acid copolymers that inhibit autoantigen-specific T cell responses and suppress experimental autoimmune encephalomyelitis
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DOI：
10.1172/jci200215402
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发表时间：
2002-06-01
影响因子：
15.9
通讯作者：
Strominger, JL
中科院分区：
文献类型：
--
作者：
Fridkis-Hareli, M;Santambrogio, L;Strominger, JL
共聚物1 （Cop 1, Copaxone [Teva Marion Partners, Kansas City, Missouri, USA]）是一种随机氨基酸共聚物，由酪氨酸(Y)、谷氨酸(E)、丙氨酸(a)和赖氨酸(K)组成，可使复发缓解型多发性硬化症（MS）患者的复发频率降低30%。基于髓鞘碱性蛋白（MBP） 85-99免疫优势表位和ms相关HLA-DR2 （DRB1*1501）结合袋的锚定残基性质，采用固相化学方法合成了新型随机四氨基酸共聚物。Poly (Y， F， A， K) （YFAK）比未标记的MBP 85-99或任何其他共聚物（包括Cop 1）更有效地抑制生物素化的MBP 86-100表位与HLA-DR2分子的结合。此外，YFAK和poly (F， A， K) （FAK）在抑制MBP 85-99特异性hla - dr2限制性T细胞克隆方面比Cop 1更有效。最重要的是，这些新型共聚物比Cop 1更有效地抑制实验性自身免疫性脑脊髓炎，这种脑源性表位为PLP 139-151的易感小鼠SJL/J（H-2s）菌株诱导的实验性自身免疫性脑脊髓炎。因此，根据人免疫优势表位MBP 85-99的结合基序和HLA-DR2的结合袋设计的随机合成共聚物可能比Cop 1更有利于治疗MS。
Copolymer 1 (Cop 1, Copaxone [Teva Marion Partners, Kansas City, Missouri, USA]), a random amino acid copolymer of tyrosine (Y), glutamic acid (E), alanine (A), and lysine (K), reduces the frequency of relapses by 30% in relapsing-remitting multiple sclerosis (MS) patients. In the present study, novel random four-amino acid copolymers, whose design was based on the nature of the anchor residues of the immunodominant epitope of myelin basic protein (MBP) 85-99 and of the binding pockets of MS-associated HLA-DR2 (DRB1*1501), have been synthesized by solid-phase chemistry. Poly (Y, F, A, K) (YFAK) inhibited binding of the biotinylated MBP 86-100 epitope to HLA-DR2 molecules more efficiently than did either unlabeled MBP 85-99 or any other copolymer including Cop 1. Moreover, YFAK and poly (F, A, K) (FAK) were much more effective than Cop 1 in inhibition of MBP 85-99-specific HLA-DR2-restricted T cell clones. Most importantly, these novel copolymers suppressed experimental autoimmune encephalomyelitis, induced in the susceptible SJL/J(H-2s) strain of mice with the encephalitogenic epitope PLP 139-151, more efficiently than did Cop 1. Thus, random synthetic copolymers designed according to the binding motif of the human immunodominant epitope MBP 85-99 and the binding pockets of HLA-DR2 might be more beneficial than Cop 1 in treatment of MS.