Clinical amelioration of murine lupus by a peptide based on the complementarity determining region-1 of an autoantibody and by cyclophosphamide: Similarities and differences in the mechanisms of action

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibodies and systemic clinical manifestations. In this study we investigated the beneficial effects on murine lupus accomplished by a peptide based on the sequence of the complementarity-determining region 1 of an anti-DNA autoantibody (hCDR1) when given alone or in combination with cyclophosphamide (CYC), and determined the mechanisms underlying those effects. SLE-afflicted (NZB x NZW) F1 mice were treated for 12 weeks with injections of hCDR1, CYC or a combination of both drugs. We found that hCDR1 and CYC ameliorated serological and renal manifestations of the diseased mice, down-regulated interferon-γ and interleukin-10, and up-regulated transforming growth factor-β. These effects were associated with an increment of naive CD4⁺ cells at the expense of the number of CD4⁺ cells with the memory/activated phenotype. Further, the number of CD8⁺ cells in the diseased mice was increased by the two drugs, resulting in a significant decrease in the CD4 : CD8 ratio. However, whereas the frequency and activity of CD4⁺ CD25⁺ CD45RB^low regulatory T cells and the expression of cytotoxic T-lymphocyte antigen 4 (CTLA-4) in CD4⁺ cells were up-regulated by hCDR1 treatment, they were minimally affected following treatment with CYC. CTLA-4 played an important role in the activity of the hCDR1-induced CD4⁺ CD25⁺ cells as manifested by down-regulation of CD28 expression, decrease of activation-induced apoptosis, and modulation of the cytokine profile in CD4⁺ CD25^- cells derived from SLE-afflicted mice. Thus, although the two drugs have similar ameliorative effects, hCDR1 but not CYC elicits regulatory pathways that are of importance for tolerance induction in SLE.