Elmann Anat, Sharabi Amir, Dayan Molly, Zinger Heidy, Ophir Ron, Mozes Edna
The Weizmann Institute of Science, Rehovot, Israel.
Arthritis Rheum. 2007 Jul;56(7):2371-81. doi: 10.1002/art.22736.
To identify genes that are differently expressed in (NZB x NZW)F(1) mice with established lupus compared with healthy controls, and to determine how gene expression is affected by treatment with hCDR1 (Edratide), a peptide synthesized on the basis of the sequence of the first complementarity-determining region (CDR1) of an autoantibody.
RNA was extracted from spleen cells of young, disease-free mice and of older mice with systemic lupus erythematosus (SLE) that were treated with hCDR1 or with vehicle alone. Gene expression was assessed using the DNA microarray technique and verified by real-time reverse transcriptase-polymerase chain reaction (RT-PCR).
In mice with SLE, numerous genes showed increased or decreased expression relative to that in the disease-free controls. Treatment with hCDR1 restored the expression of many of these genes to control levels. Real-time RT-PCR verified that in diseased mice RNA transcripts of Tnfsf4, Il5ra, Zbtb20, and Nid1 were up-regulated, while transcripts of Tfpi and S100a8 were down-regulated, and confirmed the effects of hCDR1 on the expression of those genes. Kidney immunostaining demonstrated that the up-regulated expression of OX40 ligand, which is a protein product of the gene tumor necrosis factor (ligand) superfamily member 4, in diseased mice was reduced by hCDR1.
Expression of numerous genes in mice with SLE differs from that in young, disease-free control mice. Treatment with hCDR1 restores the expression of 22% of these genes to levels similar to those in controls. Thus, one of the mechanisms by which hCDR1 exerts its beneficial effects on the clinical symptoms of SLE is through regulation of gene expression.
鉴定与健康对照相比，已患狼疮的（新西兰黑鼠×新西兰白鼠）F1代小鼠中差异表达的基因，并确定基因表达如何受到hCDR1（依德瑞肽）治疗的影响，hCDR1是一种基于自身抗体的第一个互补决定区（CDR1）序列合成的肽。
从年轻、无病小鼠以及患有系统性红斑狼疮（SLE）的老年小鼠的脾细胞中提取RNA，这些患有SLE的老年小鼠分别接受hCDR1治疗或仅接受赋形剂治疗。使用DNA微阵列技术评估基因表达，并通过实时逆转录聚合酶链反应（RT-PCR）进行验证。
在患有SLE的小鼠中，相对于无病对照，许多基因的表达呈现增加或减少。hCDR1治疗使其中许多基因的表达恢复到对照水平。实时RT-PCR证实，在患病小鼠中，肿瘤坏死因子（配体）超家族成员4基因的蛋白产物OX40配体的RNA转录本上调，而组织因子途径抑制物（TFPI）和S100钙结合蛋白A8（S100a8）的转录本下调，并证实了hCDR1对这些基因表达的影响。肾脏免疫染色表明，hCDR1可降低患病小鼠中OX40配体的上调表达。
患有SLE的小鼠中许多基因的表达与年轻的无病对照小鼠不同。hCDR1治疗可使这些基因中的22%的表达恢复到与对照相似的水平。因此，hCDR1对SLE临床症状发挥有益作用的机制之一是通过调节基因表达。
