The Tolerogenic Peptide, hCDR1, Down-Regulates the Expression of Interferon-α in Murine and Human Systemic Lupus Erythematosus

Abstract

BackgroundThe tolerogenic peptide, hCDR1, ameliorated manifestations of systemic lupus erythematosus (SLE) via the immunomodulation of pro-inflammatory and immunosuppressive cytokines and the induction of regulatory T cells. Because type I interferon (IFN-α) has been implicated to play a role in SLE pathogenesis, we investigated the effects of hCDR1 on IFN-α in a murine model of SLE and in human lupus.Methodology/Principal Findings(NZBxNZW)F1 mice with established SLE were treated with hCDR1 (10 weekly injections). Splenocytes were obtained for gene expression studies by real-time RT-PCR. hCDR1 down-regulated significantly IFN-α gene expression (73% inhibition compared to vehicle treated mice, p = 0.002) in association with diminished clinical manifestations. Further, hCDR1 reduced, in vitro, IFN-α gene expression in peripheral blood mononuclear cells (PBMC) of 10 lupus patients (74% inhibition compared to medium, p = 0.002) but had no significant effects on the expression levels of IFN-α in PBMC of primary anti-phospholipid syndrome patients or of healthy controls. Lupus patients were treated for 24 weeks with hCDR1 (5) or placebo (4) by weekly subcutaneous injections. Blood samples collected, before and after treatment, were frozen until mRNA isolation. A significant reduction in IFN-α was determined in hCDR1 treated patients (64.4% inhibition compared to pretreatment expression levels, p = 0.015). No inhibition was observed in the placebo treated patients. In agreement, treatment with hCDR1 resulted in a significant decrease of disease activity. IFN-α appears to play a role in the mechanism of action of hCDR1 since recombinant IFN-α diminished the immunomodulating effects of hCDR1 on IL-1β, TGFβ and FoxP3 gene expression.Conclusions/SignificanceWe reported previously that hCDR1 affected various cell types and immune pathways in correlation to disease amelioration. The present studies demonstrate that hCDR1 is also capable of down-regulating significantly (and specifically to lupus) IFN-α gene expression. Thus, hCDR1 has a potential role as a novel, disease specific treatment for lupus.

Upcoming biological therapies in systemic lupus erythematosus

“…Preliminary studies in humans confirmed data from animal models showing that edratide downregulates pathogenic cytokines and apoptosis, IFN-a gene expression, and upregulates immunosuppressive molecules and Tregs cells in peripheral blood [29][30][31].…”

Tregitope Peptides: The Active Pharmaceutical Ingredient of IVIG?

“…Immunoglobulin G has been known to exhibit tolerogenic properties for decades, and a number of previous publications have alluded to the potential presence of regulatory or “suppressor” epitopes in IgG constant domains, whether located to the constant (Fc) or binding region (Fab). For example, Baxevanis et al described a tolerizing effect of Ig Fc that was localized to the CH2 region, consistent with the location of several Tregitopes [ 15 ]; a peptide isolated from the Fab region of an anti-idiotypic peptide (which overlaps one of the subsequently identified Tregitopes) suppressed Systemic Lupus Erythematosis in humans and in mice [ 16 , 17 ]; a peptide derived from the highly conserved J region framework was shown by Warnke et al to induce Tregs to expand and suppress immune responses in suppressor assays [ 18 ].…”

Peptide-Based Vaccination Therapy for Rheumatic Diseases

“…Waisman et al reported that peptides from CDRs of pathogenic anti-DNA mAbs could prevent autoantibody production and downregulate autoreactive T cell responses, representing a potential treatment for SLE [184,185]. Several other studies further revealed that a tolerogenic peptide derived from the CDR1 of a human anti-DNA autoantibody (hCDR1) could ameliorate lupus by inducing Tregs and suppressing the activation of autoreactive cells in lupus animal models [186,187]. Several possible mechanisms have also been proposed to explain the therapeutic role of hCDR1 in SLE, such as TGF-β-mediated suppression of autoreactive T cells and downregulation of transcription factors responsible for negative regulation of T cell activation [188,189].…”