Protein microarrays guide tolerizing DNA vaccine treatment of autoimmune encephalomyelitis
Protein microarrays guide tolerizing DNA vaccine treatment of autoimmune encephalomyelitis
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DOI：
10.1038/nbt859
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发表时间：
2003-09-01
影响因子：
46.9
通讯作者：
Steinman, L
中科院分区：
文献类型：
--
作者：
Robinson, WH;Fontoura, P;Steinman, L
自身免疫反应的多样性对抗原特异性耐受治疗的发展提出了严峻的挑战。我们开发了“髓鞘蛋白质组”微阵列来描述实验性自身免疫性脑脊髓炎（EAE）（多发性硬化症（MS）模型）中自身抗体反应的演变。急性EAE中自身抗体反应的多样性增加预示着更严重的临床过程。慢性EAE与先前未描述的自身反应性B细胞反应的广泛分子内和分子间表位扩散相关。急性EAE中靶向的自身抗原的阵列分析用于指导选择要并入表达质粒中的自身抗原cDNA，以便产生耐受性疫苗。编码大量阵列确定的髓鞘靶点的耐受性DNA疫苗在治疗已建立的EAE和减少自身反应性B细胞应答的表位扩散方面被证明是上级的。自身抗体反应的蛋白质组学监测提供了一种有用的方法来监测自身免疫性疾病，并开发和定制疾病和患者特异性耐受性DNA疫苗。
The diversity of autoimmune responses poses a formidable challenge to the development of antigen-specific tolerizing therapy. We developed 'myelin proteome' microarrays to profile the evolution of autoantibody responses in experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS). Increased diversity of autoantibody responses in acute EAE predicted a more severe clinical course. Chronic EAE was associated with previously undescribed extensive intra- and intermolecular epitope spreading of autoreactive B-cell responses. Array analysis of autoantigens targeted in acute EAE was used to guide the choice of autoantigen cDNAs to be incorporated into expression plasmids so as to generate tolerizing vaccines. Tolerizing DNA vaccines encoding a greater number of array-determined myelin targets proved superior in treating established EAE and reduced epitope spreading of autoreactive B-cell responses. Proteomic monitoring of autoantibody responses provides a useful approach to monitor autoimmune disease and to develop and tailor disease- and patient-specific tolerizing DNA vaccines.