Soluble MOG35-55/I-A(b) dimers ameliorate experimental autoimmune encephalomyelitis by reducing encephalitogenic T cells.
Soluble MOG35-55/I-A(b) dimers ameliorate experimental autoimmune encephalomyelitis by reducing encephalitogenic T cells.
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DOI：
10.1371/journal.pone.0047435
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Wu X
中科院分区：
文献类型：
--
作者：
Gong Y;Wang Z;Liang Z;Duan H;Ouyang L;Yu Q;Xu Z;Shen G;Weng X;Wu X
C57 BL/6小鼠中MOG 35 -55肽诱导的实验性自身免疫性脑脊髓炎（EAE）模型是探索T细胞介导的自身免疫性疾病的治疗方法的有用动物模型，因为已经定义了显性T细胞表位。合理的是，抗原特异性免疫抑制可以通过使用MHC-肽复合物作为特异性TCR配体来诱导，所述TCR配体在不存在共刺激的情况下与自身反应性T细胞相互作用。在本研究中，构建了可溶性二价MOG 35 -55/I-Ab融合蛋白（MOG 35 -55/I-Ab二聚体）以特异性靶向EAE小鼠中的自身反应性CD 4 + T细胞。腹腔注射MOG 35 -55/I-Ab二聚体可通过减少小鼠CNS中EAE相关炎症和减少外周淋巴器官中致脑炎性Th 1和Th 17细胞，显著延迟和改善EAE症状。我们观察到，在用MOG 35 - 55肽体外活化后，浓度为1.2 nM的二聚体干预抑制MOG 35 - 55肽特异性2D 2转基因T细胞（2D 2 T细胞）增殖超过90%。发现这种抗原特异性二聚体介导的抑制中涉及的机制是自身反应性CD 4 + T细胞下调TCR-CD 3表达以及上调膜结合TGF-β（mTGF-β）和IL-10抑制性细胞因子的表达。总的来说，我们的数据表明，可溶性二价MHC II类分子可以消除致病性T细胞在EAE。此外，我们的数据表明，这种策略可能提供一个有效的和临床上有用的选择，以治疗自身免疫性疾病。
The MOG35-55 peptide-induced experimental autoimmune encephalomyelitis (EAE) model in C57BL/6 mice is a useful animal model to explore therapeutic approaches to T cell-mediated autoimmune diseases because the dominant T-cell epitope(s) have been defined. It is rational that antigen-specific immunosuppression can be induced by using MHC-peptide complexes as specific TCR ligand(s) that interact with autoreactive T cells in the absence of co-stimulation. In this study, a soluble divalent MOG35-55/I-Ab fusion protein (MOG35-55/I-Ab dimer) was constructed to specifically target the autoreactive CD4+ T cells in the EAE mouse. Intraperitoneal administration of the MOG35-55/I-Ab dimer significantly delayed and ameliorated EAE symptoms by reducing EAE-related inflammation in the mouse CNS and reducing encephalitogenic Th1 and Th17 cells in the peripheral lymphoid organs. We observed that dimer intervention at a concentration of 1.2 nM suppressed MOG35-55 peptide-specific 2D2 transgenic T cells (2D2 T cells) proliferation by over 90% after in vitro activation with MOG35-55 peptide. The mechanisms involved in this antigen-specific dimer-mediated suppression were found to be downregulated TCR-CD3 expression as well as upregulated expression of membrane-bound TGF-β (mTGF-β) and IL-10 suppressive cytokines by the autoreactive CD4+ T cells. Collectively, our data demonstrates that soluble divalent MHC class II molecules can abrogate pathogenic T cells in EAE. Furthermore, our data suggests that this strategy may provide an efficient and clinically useful option to treat autoimmune diseases.
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影响因子：
15.3
作者：
ABASTADO, JP;LONE, YC;KOURILSKY, P
通讯作者：
KOURILSKY, P
影响因子：
6.2
作者：
Rickert, Uta;Welke, Judith;Zavazava, Nicholas
通讯作者：
Zavazava, Nicholas
影响因子：
3.3
作者：
Offner, Halina;Sinha, Sushmita;Burrows, Gregory G.;Ferro, Adolph J.;Vandenbark, Arthur A.
通讯作者：
Vandenbark, Arthur A.
DOI：
10.1073/pnas.90.14.6671
发表时间：
1993-07-15
影响因子：
11.1
作者：
DALPORTO, J;JOHANSEN, TE;SCHNECK, JP
通讯作者：
SCHNECK, JP
影响因子：
32.4
作者：
Labrecque, N;Whitfield, LS;Mathis, D
通讯作者：
Mathis, D