Background/Purpose:

The tolerogenic peptide, designated hCDR1, was shown to ameliorate manifestations of systemic lupus erythematosus (SLE)  via down-regulation of pro-inflammatory cytokines, up-regulation of immunosuppressive cytokines and molecules  and  the induction of regulatory T cells.  Because type I interferon (IFN-a) has been implicated to play a major role in the pathogenesis of SLE, in the present studies we investigated the effects of hCDR1 on IFN-a in a murine model of SLE and in human lupus.

Methods:

(NZBxNZW)F1 female mice with established SLE manifestations were treated with hCDR1 (10 weekly subcutaneously injections) or  with the vehicle alone. The effects on anti-dsDNA antibody levels, proteinuria and kidney immunohistology were assessed. Splenocytes were obtained for gene expression studies. Peripheral blood lymphocytes (PBL) of lupus patients (10), primary anti-phospholipid syndrome (APS) patients (5) and healthy controls (5) were incubated in vitro for 48 hours with hCDR1 or medium prior to gene expression assays. Lupus patients were treated for 26 weeks with hCDR1 (5) or placebo (4) in a Phase II clinical trial by weekly subcutaneous injections. Disease activity was assessed using SLEDAI-2K and BILAG scores [1]. Blood samples were collected, before and after treatment, in PAXgene tubes and frozen until mRNA isolation. Gene expression of IFN-a was determined by real-time RT-PCR.

Results:

Treatment of (NZBxNZW)F1 SLE afflicted mice with hCDR1 down-regulated significantly IFN-a gene expression (73% inhibition compared to vehicle, p= 0.002). The latter was associated with diminished anti-dsDNA titers as well as proteinuria and glomerular immune complex deposit levels. Further, hCDR1 reduced, in vitro, the IFN-a gene expression in PBL of lupus patients (74% inhibition compared to medium, p=0.002). hCDR1 had no significant effects on the expression levels of IFN-a in PBL of primary APS patients or of healthy controls. Moreover, a significant reduction in IFN-a was determined in PBL of lupus patients that were treated with hCDR1 for 26 weeks (64.4% inhibition compared to pretreatment expression levels, p=0.015).  No inhibition of IFN-a expression was observed in PBL of placebo treated patients.  In agreement, as previously reported, treatment with hCDR1, but not with placebo, resulted in a significant decrease of disease activity as determined by the BILAG and SLEDAI-2K scores [1].

Conclusion:

Treatment with hCDR1 resulted in a significant amelioration of lupus manifestations in murine models. Studies of a limited number of lupus patients indicated beneficial effects in hCDR1 treated patients. We reported previously that hCDR1 affected various cell types and immune pathways involved in the pathogenesis of SLE. The present studies demonstrate that hCDR1 is also capable of down-regulating significantly (and specifically to lupus) IFN-a that has been recently considered as a target for SLE therapy.  Thus, hCDR1 has a potential role as a novel, disease specific treatment for human lupus.

[1] Journal of Autoimmunity, 33 (2009) 77-82.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-tolerogenic-peptide-down-regulates-the-expression-of-interferon-a-in-murine-and-human-systemic-lupus-erythematosus/