Amelioration of lupus manifestations by a peptide based on the complementarity determining region 1 of an autoantibody in severe combined immunodeficient (SCID) mice engrafted with peripheral blood lymphocytes of systemic lupus erythematosus (SLE) patients

Abstract

SUMMARYA peptide based on the complementarity determining region (CDR)1 of a human monoclonal anti-DNA autoantibody (hCDR1) was shown to either prevent or treat an already established murine lupus in systemic lupus erythematosus (SLE)-prone mice or in mice with induced experimental SLE. The present study was undertaken to determine the therapeutic potential of hCDR1 in a model of lupus in severe combined immunodeficient (SCID) mice engrafted with peripheral blood lymphocytes (PBL) of patients with SLE. To this end, PBL obtained from lupus patients were injected intraperitoneally into two equal groups of SCID mice that were treated either with the hCDR1 (50 m g/mouse) once a week for 8 weeks, or with a control peptide. Mice were tested for human IgG levels, anti-dsDNA autoantibodies, anti-tetanus toxoid antibodies and proteinuria. At sacrifice, the kidneys of the successfully engrafted mice were assessed for human IgG and murine complement C3 deposits . Of the 58 mice transplanted with PBL of SLE patients, 38 (66%) were engrafted successfully. The mice that were treated with the control peptide developed human dsDNA-specific antibodies. Treatment with hCDR1 down-regulated the latter significantly. No significant effect of the treatment on the levels of antitetanus toxoid antibodies could be observed. Treatment with hCDR1 resulted in a significant amelioration of the clinical features manifested by proteinuria, human IgG complex deposits as well as deposits of murine complement C3. Thus, the hCDR1 peptide is a potential candidate for a novel specific treatment of SLE patients.

The tolerogenic peptide hCDR1 downregulates pathogenic cytokines and apoptosis and upregulates immunosuppressive molecules and regulatory T cells in peripheral blood mononuclear cells of lupus patients

“…Moreover, we were able to establish a human model of SLE by transferring PBMC of lupus patients into severe combined immunodeficient (SCID) mice [21]. Treatment with hCDR1 ameliorated serologic (human anti-DNA antibodies) and clinical lupus-related manifestations in the latter SCID model of human SLE [22]. In view of the various immunomodulatory effects of hCDR1 in the murine models of lupus, it was of interest to determine the effects of the peptide on PBMC obtained from SLE patients.…”

Elimination of autoreactive B cells in humanized SCID mouse model of SLE

“…Further on, the successfully humanized SCID mice develop many symptoms of the human lupus (anti-dsDNA antibodies, skin lesions, proteinuria, and glomerulonephritis, etc.) and are a suitable model to investigate the efficiency of therapeutic B-cell depletion [39][40][41]. In the present study, we established a humanized SCID model to investigate the effect of the treatment with DNA-like chimera on the pathogenesis of human SLE.…”

Anti-DNA idiotypes: from induction of disease to novel therapeutical approaches

“…Further studies confirmed the importance of the idiotypic epitopes that later on were identified as the sequence of amino-acid peptides residing in the antigen binding site (CDR) regions 1 or 3 [24][25][26].…”