Systemic immunotherapy delays photoreceptor cell loss and prevents vascular pathology in Royal College of Surgeons rats
Systemic immunotherapy delays photoreceptor cell loss and prevents vascular pathology in Royal College of Surgeons rats
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发表时间：
2012-09
期刊：
影响因子：
2.2
通讯作者：
G. Adamus;Shaomei Wang;Madison H. Kyger;A. Worley;B. Lu;G. Burrows
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作者：
G. Adamus;Shaomei Wang;Madison H. Kyger;A. Worley;B. Lu;G. Burrows
目的退行性视网膜病变，包括视网膜色素变性、年龄相关性视网膜变性、自身免疫性视网膜病变及相关疾病，影响着全世界数以百万计的人。目前，这些疾病中的大多数都没有有效的治疗方法。在皇家外科学院(RCS)大鼠视网膜变性模型中，我们研究了系统性重组T细胞受体配体(RTL)免疫疗法预防视网膜变性和血管损伤的作用。方法RCS大鼠在视网膜感光细胞退变时或退变开始后每天或隔日皮下注射RTL2 2 0光感受器间视黄醇结合蛋白(IRBP)多肽或不含多肽的RTL10 1，连续13周。制作视网膜横切面和整体铺片，以确定组织病理学、血管渗漏和血管复合体的形成。免疫荧光研究评估了治疗后视网膜中的小胶质细胞和单核细胞趋化蛋白-1趋化因子。进行视动力学检查以确定视力。结果RTL220全身用药组大鼠外核层(ONL)厚度减少，核数显着高于RTL101组和赋形剂对照组。RTL220在防止视网膜血管渗漏和形成异常血管复合体方面也是有效的，即使在退变过程开始后进行治疗也是如此。视力测量显示，在60岁和90岁时，接受RTL220治疗的大鼠的表现明显好于RTL101和未治疗的年龄匹配的对照组。生物分布研究表明，RTL220从给药部位清除缓慢。此外，RTL220处理的视网膜显著减少了视网膜下间隙中激活的小胶质细胞的数量，减少了视网膜中单核细胞趋化蛋白-1的产生，抑制了T细胞反应，并降低了抗光感受器间视黄醇结合蛋白自身抗体的效价。单独使用对照RTL101(没有特定的多肽)或赋形剂的治疗不能抑制小胶质细胞的激活，也不能保护光感受器或血管系统。结论RTL治疗可提高RTL大鼠视感受器细胞存活率，保护血管系统，提高视功能。用RTLS靶向慢性自身免疫可以成为延缓视网膜变性的一种有效的治疗选择。对于视网膜退行性疾病的长期治疗，单独或与其他药物联合皮下注射RTL可能是一个有吸引力的选择。
Purpose Degenerative retinopathies, including retinitis pigmentosa, age-related retinal degeneration, autoimmune retinopathy, and related diseases affect millions of people around the world. Currently, there is no effective treatment for most of those diseases. We investigated systemic recombinant T-cell receptor ligand (RTL) immunotherapy for preventing retinal degeneration and vascular damage in the Royal College of Surgeons (RCS) rat model of retinal degeneration. Methods RCS rats were treated with RTL220 tethered to interphotoreceptor retinoid binding protein (IRBP) peptide or control RTL101 without peptide by subcutaneous administration starting at the onset of photoreceptor degeneration or after the degenerative process began daily or every other day and performed for a 13-week period. The retinal cross sections and whole mounts were prepared to determine histopathology, leaking vessels, and formation of vascular complexes. Immunofluorescent studies evaluated microglia and monocyte chemoattractant protein-1 chemokine in treated retinas. Optokinetic studies were performed to determine visual acuity. Results Systemic treatment with RTL220 prevented decreases in outer nuclear layer (ONL) thickness and showed a significantly higher number of nuclei than control rats treated with RTL101 or vehicle. RTL220 was also effective in protecting retinal vasculature from leakage and the formation of abnormal vascular complexes even when the treatment was administered after the degenerative process was initiated. Visual acuity measurement showed that rats treated with RTL220 performed significantly better than those with RTL101 and untreated age-matched controls at P60 and P90. Biodistribution studies showed that RTL220 cleared slowly from the administration site. Moreover, RTL220-treated retinas had a significantly reduced number of activated microglia in the subretinal space, decreased monocyte chemoattractant protein-1 production in the retina, inhibited T-cell responses, and reduced anti-interphotoreceptor retinoid binding protein autoantibody titers. Treatment with the control RTL101 (without a specific peptide tethered) or vehicle alone did not inhibit microglia activation or protect photoreceptors or vasculature. Conclusions RTL therapy augmented photoreceptor cell survival, protected vasculature, and increased visual function in the RTL rat. Targeting chronic autoimmunity with RTLs can be an effective therapeutic alternative in delaying retinal degeneration. Subcutaneous delivery of RTLs alone or combined with other drugs could be an attractive option for long-term therapy for retinal degenerative diseases.