Regulation of encephalitogenic T cells with recombinant TCR ligands
Regulation of encephalitogenic T cells with recombinant TCR ligands
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DOI：
10.4049/jimmunol.164.12.6366
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发表时间：
2000-06-15
影响因子：
4.4
通讯作者：
Offner, H
中科院分区：
文献类型：
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作者：
Burrows, GG;Adlard, KL;Offner, H
我们先前已经描述了负载有对致脑炎性T细胞具有有效抑制活性的游离抗原肽的重组MHC II类β 1和α 1结构域。我们现在已经产生了单链构建体，其中肽Ag在与连接的pi和al结构域相同的外显子内被遗传编码，克服了肽Ag从肽结合裂缝置换的问题。我们在此描述了重组TCR配体（RTL）的临床作用，该配体由大鼠RT1.B β 1 α 1结构域组成，该结构域共价连接至豚鼠髓鞘碱性蛋白（RTL-201）的72 - 89肽、大鼠髓鞘碱性蛋白（RTL-200）的相应72 -89肽或心肌肌球蛋白肽CM-2（RTL-203）。只有RTL-201具有预防和治疗主动或被动实验性自身免疫性脑脊髓炎的能力。实验性自身免疫性脑脊髓炎的改善与选择性抑制Ag刺激的淋巴结T细胞的增殖反应和细胞因子产生以及显著减少浸润CNS的致脑炎和募集的炎性细胞的数量有关，这种精细的选择性抑制作用可以在仅相差一个甲基的分子之间观察到（在髓鞘碱性蛋白肽的位置80处RTL-200（苏氨酸）和RTL-20（丝氨酸）之间的单个氨基酸残基差异），这些新的RTLs为开发用于治疗自身免疫性疾病的有效和选择性的人诊断和治疗剂提供了平台。
We have previously described recombinant MHC class II beta i and alpha l domains loaded with free antigenic peptides with potent inhibitory activity on encephalitogenic T cells. We have now produced single-chain constructs in which the peptide Ag is genetically encoded within the same exon as the linked pi and al domains, overcoming the problem of displacement of peptide Ag from the peptide binding cleft. We here describe clinical effects of recombinant TCR ligands (RTLs) comprised of the rat RT1.B beta 1 alpha 1 domains covalently linked to the 72-89 peptide of guinea pig myelin basic protein (RTL-201), to the corresponding 72-89 peptide from rat myelin basic protein (RTL-200), or to cardiac myosin peptide CM-2 (RTL-203). Only RTL-201 possessed the ability to prevent and treat active or passive experimental autoimmune encephalomyelitis, Amelioration of experimental autoimmune encephalomyelitis was associated with a selective inhibition of proliferation response and cytokine production by Ag-stimulated lymph node T cells and a drastic reduction in the number of encephalitogenic and recruited inflammatory cells infiltrating the CNS, The exquisitely selective inhibition could be observed between molecules that differ by a single methyl group (the single amino acid residue difference between RTL-200 (threonine) and RTL-20 (serine) at position 80 of the myelin basic protein peptide), These novel RTLs provide a platform for developing potent and selective human diagnostic and therapeutic agents for treatment of autoimmune disease.