Modulation of murine systemic lupus erythematosus with peptides based on complementarity determining regions of a pathogenic anti-DNA monoclonal antibody

Abstract

Experimental systemic lupus erythematosus (SLE) can be induced in naive mice by immunization with a murine monoclonal anti-DNA antibody (mAb), 5G12, that bears a major idiotype designated 16͞6 Id. Strain-dependent differences were observed in the proliferative responses of lymph node cells of mice immunized with two peptides based on the sequences of the complementarity determining region (CDR) 1 and 3 of mAb 5G12. The capacity of the peptides to bind to major histocompatibility complex class II molecules correlated with the proliferative responses. Immunization of high responder strains with the CDR-based peptides led to production of autoantibodies and clinical manifestations characteristic to experimental SLE. The CDR-based peptides could prevent autoantibody production in neonatal mice that were immunized later either with the peptide or with the pathogenic autoantibody. Furthermore, the peptides inhibited specific proliferation of lymph node cells of mice immunized with the same peptide, with mAb 5G12 or with the human mAb anti-DNA, 16͞6 Id. Thus, the CDR-based peptides are potential candidates for therapy of SLE.

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

“…2 Mice at the age of 6Á5 months (n ¼ 13 to n ¼ 23/group) were treated once a week with weekly injections of the vehicle (s.c.), hCDR1 (s.c.) and/or CYC (i.p.) during 12 weeks.…”

“…2,3 The peptides were shown to be capable of down-regulating autoimmune responses associated with SLE. 2,4 Furthermore, the peptides were capable of either preventing or treating an established disease that was either induced or developed spontaneously in mice. [4][5][6][7] The hCDR1 (Edratide) is a peptide that is based on the CDR1 of the human anti-DNA monoclonal antibody.…”

“…The standard therapy regimens are based mainly on immunosuppressive Amir Sharabi, 1 Hava Azulai, 2 Zev M. Sthoeger 2 …”

The negative regulators Foxj1 and Foxo3a are up‐regulated by a peptide that inhibits systemic lupus erythematosus‐associated T cell responses

“…4B) Foxo3a expression compared with T cells derived from 16/6Id-immunized mice that were not treated with hCDR1. To verify the observed upregulation of Foxj1 and Foxo3a following in vivo treatment with hCDR1, we studied the expression levels of these transcription factors in lupus prone (NZBÂNZW)F1 mice in which treatment with hCDR1 was previously shown [3][4][5][6][7] to ameliorate SLE manifestations in association with down-regulation of IFN-c secretion. To this end, T cells were purified from splenocytes of (NZBÂNZW)F1 mice that were harvested after 10 weeks of treatment (once a week) with either hCDR1 or the vehicle (PBS).…”

“…The 16/ 6Id-induced disease in mice is manifested by high levels of autoantibodies (anti-dsDNA and anti-nuclear protein Ab), and by SLE-associated clinical symptoms [1,2]. Furthermore, a peptide based on the sequences of the complementarity determining region (CDR)1 of the human 16/6Id was shown to down-regulate autoreactive T cell responses in vitro and in vivo, and to ameliorate the clinical (e.g., proteinuria, leukopenia) and serological (anti-dsDNA Ab) manifestations, histopathological findings and kidney IgG deposits of spontaneous (NZB/NZW)F1 and induced models of SLE in mice [3][4][5][6][7]. The latter was associated with downregulation of the cytokines that play a key role in the pathogenesis of lupus (e.g., IFN-c, IL-10, IL-1) and with an up-regulation of the immunosuppressive cytokine TGF-b [4,5,7].…”