A Novel Approach to Reinstating Tolerance in Experimental Autoimmune Myasthenia Gravis Using a Targeted Fusion Protein, mCTA1-T146.
A Novel Approach to Reinstating Tolerance in Experimental Autoimmune Myasthenia Gravis Using a Targeted Fusion Protein, mCTA1-T146.
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DOI：
10.3389/fimmu.2017.01133
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发表时间：
2017
影响因子：
7.3
通讯作者：
Baggi F
中科院分区：
文献类型：
--
作者：
Consonni A;Sharma S;Schön K;Lebrero-Fernández C;Rinaldi E;Lycke NY;Baggi F
恢复组织特异性耐受作为治疗自身免疫性疾病的一种手段已经引起了广泛的关注。然而，尽管在自身免疫性疾病的啮齿动物模型中取得了有希望的结果，但临床上还没有确定的致耐受性疗法。在实验性自身免疫性重症肌无力（EAMG）模型中，已经报道了几种方案，其诱导对主要疾病相关抗原（神经肌肉接头处的乙酰胆碱受体（AChR））的耐受。使用完整的AChR，细胞外部分或来自受体的肽，研究人员已经报道了他们的治疗的可变成功，尽管通常需要相对大量的抗原。因此，需要更好的制剂和策略来改善耐受性诱导疗法的功效。在这里，我们报告了一种新的靶向融合蛋白携带免疫显性肽从AChR，mCTA1-T146，给予鼻内在重复微克剂量强烈抑制诱导以及正在进行的EAMG疾病的小鼠。结果证实了我们以前的发现，使用相同的融合蛋白的方法，在胶原诱导的关节炎模型中显示出对Th1和Th17自身侵袭性CD4 T细胞的显著抑制作用，并上调调节性T细胞活性，增强IL 10的产生。在用mCTA1-T146鼻内处理后，在淋巴结和脾脏中可清楚地检测到TGF β、IL 10、IL 27和Foxp3的mRNA表达上调的抑制性基因特征。EAMG疾病的改善伴随着减少肌肉AChR的损失和较低水平的抗AChR血清抗体。我们认为这种靶向高效融合蛋白mCTA1-T146是一种有希望的用于重症肌无力患者临床评估的候选蛋白。
Reinstating tissue-specific tolerance has attracted much attention as a means to treat autoimmune diseases. However, despite promising results in rodent models of autoimmune diseases, no established tolerogenic therapy is clinically available yet. In the experimental autoimmune myasthenia gravis (EAMG) model several protocols have been reported that induce tolerance against the prime disease-associated antigen, the acetylcholine receptor (AChR) at the neuromuscular junction. Using the whole AChR, the extracellular part or peptides derived from the receptor, investigators have reported variable success with their treatments, though, usually relatively large amounts of antigen has been required. Hence, there is a need for better formulations and strategies to improve on the efficacy of the tolerance-inducing therapies. Here, we report on a novel targeted fusion protein carrying the immunodominant peptide from AChR, mCTA1–T146, which given intranasally in repeated microgram doses strongly suppressed induction as well as ongoing EAMG disease in mice. The results corroborate our previous findings, using the same fusion protein approach, in the collagen-induced arthritis model showing dramatic suppressive effects on Th1 and Th17 autoaggressive CD4 T cells and upregulated regulatory T cell activities with enhanced IL10 production. A suppressive gene signature with upregulated expression of mRNA for TGFβ, IL10, IL27, and Foxp3 was clearly detectable in lymph node and spleen following intranasal treatment with mCTA1–T146. Amelioration of EAMG disease was accompanied by reduced loss of muscle AChR and lower levels of anti-AChR serum antibodies. We believe this targeted highly effective fusion protein mCTA1–T146 is a promising candidate for clinical evaluation in myasthenia gravis patients.
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影响因子：
16.6
作者：
Burton, Bronwen R.;Britton, Graham J.;Fang, Hai;Verhagen, Johan;Smithers, Ben;Sabatos-Peyton, Catherine A.;Carney, Laura J.;Gough, Julian;Strobel, Stephan;Wraith, David C.
通讯作者：
Wraith, David C.
影响因子：
12.8
作者：
Aricha, Revital;Reuveni, Debby;Souroujon, Miriam C.
通讯作者：
Souroujon, Miriam C.
影响因子：
12.8
作者：
Gradolatto, Angeline;Nazzal, Dani;Berrih-Aknin, Sonia
通讯作者：
Berrih-Aknin, Sonia
影响因子：
13.8
作者：
Hansson, Charlotta;Schon, Karin;Lycke, Nils Y.
通讯作者：
Lycke, Nils Y.
影响因子：
--
作者：
Hasselberg, Annemarie;Schon, Karin;Lycke, Nils
通讯作者：
Lycke, Nils