Neuroprotective Effects of Recombinant T-cell Receptor Ligand in Autoimmune Optic Neuritis in HLA-DR2 Mice
Neuroprotective Effects of Recombinant T-cell Receptor Ligand in Autoimmune Optic Neuritis in HLA-DR2 Mice
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DOI：
10.1167/iovs.11-8419
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发表时间：
2012-01-01
影响因子：
4.4
通讯作者：
Vandenbark, Arthur A.
中科院分区：
文献类型：
--
作者：
Adamus, Grazyna;Brown, Lori;Vandenbark, Arthur A.
目的.视神经炎（ON）是一种涉及视神经中的原发性炎症、脱髓鞘和轴突损伤的病症，并导致视网膜神经节细胞（RGC）凋亡死亡，这导致视力丧失的持续性。目前，没有有效的治疗方法。目的是确定重组T细胞受体配体（RTL）免疫治疗在预防人源化HLA-DR 2转基因小鼠ON中的有效性。在人源化HLA-DR 2（DR β 1* 1501）转基因小鼠中用髓鞘少突胶质细胞糖蛋白诱导实验性自身免疫性脑脊髓炎（EAE）。在ON发作时连续给予5个剂量的RTL 342 M。在不同时间点通过组织病理学评估自身免疫性ON的发展。髓鞘丢失、轴突丢失和RGC损伤的水平通过免疫荧光法检测。HLA-DR 2小鼠在EAE前2天发生慢性ON，其特征在于两个器官中的进行性神经变性。RTL 342 M显著抑制视神经和脊髓中的炎症，并提供至少30天的保护。髓鞘丢失的检查显示脱髓鞘的明显抑制和视神经中髓鞘恢复的增加。此外，RTL 342 M处理揭示了在免疫后（PI）第62天对视网膜中的视神经轴突和RGCs的神经保护作用。RTL 342 M通过阻止炎性细胞募集到视神经中来抑制EAE/ON的临床和组织学体征，并显示出对ON的神经保护作用。这些研究结果表明，这类新的T细胞耐受性药物可能用于视神经炎患者的临床应用。（Invest Ophthalmol维斯科学。2012; 53：406-412）DOI：10.1167/iovs.11-8419
PURPOSE. Optic neuritis (ON) is a condition involving primary inflammation, demyelination, and axonal injury in the optic nerve and leads to apoptotic retinal ganglion cell (RGC) death, which contributes to the persistence of visual loss. Currently, ON has no effective treatment. The goal was to determine the effectiveness of immunotherapy with recombinant T-cell receptor ligand (RTL) in preventing ON in humanized HLA-DR2 transgenic mice.METHODS. Experimental autoimmune encephalomyelitis (EAE) was induced with myelin oligodendrocyte glycoprotein in humanized HLA-DR2 (DR beta 1* 1501) transgenic mice. Five consecutive doses of RTL342M were administrated at the onset of ON. The development of autoimmune ON was assessed by histopathology at different time points. The levels of myelin loss, axonal loss, and RGC damage were examined by immunofluorescence.RESULTS. HLA-DR2 mice developed chronic ON 2 days before EAE characterized by progressive neurodegeneration in both organs. RTL342M significantly suppressed inflammation in the optic nerve and spinal cord and provided protection for at least 30 days. Examination of myelin loss showed a marked suppression of demyelination and an increase in myelin recovery in the optic nerve. Moreover, RTL342M treatment revealed a neuroprotective effect on optic nerve axons and RGCs in retinas at postimmunization (PI) day 62.CONCLUSIONS. RTL342M suppressed clinical and histologic signs of EAE/ON by preventing the recruitment of inflammatory cells into the optic nerve and showed neuroprotective effects against ON. However, to achieve full therapeutic benefit, more doses may be needed. These findings suggest a possible clinical application of this novel class of T-cell-tolerizing drugs for patients with optic neuritis. (Invest Ophthalmol Vis Sci. 2012; 53: 406-412) DOI:10.1167/iovs.11-8419