Treatment of murine lupus with cDNA encoding IFN-γR/Fc
Treatment of murine lupus with cDNA encoding IFN-γR/Fc
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DOI：
10.1172/jci10167
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发表时间：
2000-07-01
影响因子：
15.9
通讯作者：
Theofilopoulos, AN
中科院分区：
文献类型：
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作者：
Lawson, BR;Prud'homme, GJ;Theofilopoulos, AN
IFN-γ是一种多效性细胞因子，是包括狼疮在内的多种自身免疫性疾病发病机制中的关键效应分子。重要的是，在几种狼疮易感小鼠品系中IFN-γ或IFN-γ R的缺失导致疾病显著减轻，表明了治疗干预的潜力。我们评估了肌肉注射编码IFN-γ R/Fc的cDNA质粒是否可以延缓MRL-Fas（lpr）小鼠狼疮的发展和进展。当在疾病前阶段开始治疗时，特别是当注射部位电穿孔增强IFN-γ R/Fc表达时，治疗显著降低了IFN-γ的血清水平以及疾病表现（自身抗体、淋巴样增生、肾小球肾炎、死亡率）。值得注意的是，当这种治疗在晚期开始时，疾病被阻止甚至得到改善。这种疗法代表了一种罕见的疾病逆转的例子，并且使得这种非病毒基因疗法在患有狼疮（以及可能的其他自身免疫/炎症性疾病）的人类中的应用非常有希望。
IFN-gamma, a pleiotropic cytokine, is a key effector molecule in the pathogenesis of several autoimmune diseases, including lupus. Importantly, deletion of IFN-gamma or IFN-gamma R in several lupus-predisposed mouse strains resulted in significant disease reduction, suggesting the potential for therapeutic intervention. We evaluated whether intramuscular injections of plasmids with cDNA encoding IFN-gamma R/Fc can retard lupus development and progression in MRL-Fas(lpr) mice. Therapy significantly reduced serum levels of IFN-gamma, as well as disease manifestations (autoantibodies, lymphoid hyperplasia, glomerulonephritis, mortality), when treatment was initiated at the predisease stage, particularly when IFN-gamma R/Fc expression was enhanced by electroporation at the injection site. Remarkably, disease was arrested and even ameliorated when this treatment was initiated at an advanced stage. This therapy represents a rare example of disease reversal and makes application of this nonviral gene therapy in humans with lupus (and perhaps other autoimmune/inflammatory conditions) highly promising.