Altered gene expression in mice with lupus treated with edratide, a peptide that ameliorates the disease manifestations

Objective: 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.

Methods: 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).

Results: 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.

Conclusion: 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.