Peptide mimetics of anti-dsDNA idiotypes as a tool for lupus-specific IVIG preparation: specificity and efficacy in the treatment of experimental systemic lupus erythematosus

Since the idiotypic network is an important mechanism for controlling the immune repertoire, we tested anti-idiotypic modulation employing concentrated specific natural polyclonal anti-dsDNA anti-idiotypic antibodies obtained from a commercial IVIG in the treatment of experimental systemic lupus erythematosus (SLE).

To address the specificity and efficacy of affinity purified IVIG, affinity purified on peptide mimetics of anti-dsDNA idiotypes, in vitro and in vivo, as treatment for experimental lupus.

Specific natural polyclonal anti-dsDNA anti-idiotypic antibodies were affinity purified from IVIG (OMRIX Biopharmaceuticls Inc., Nes-Ziona, Israel) on an anti-dsDNA-Sepharose column constructed with anti-dsDNA idiotypes affinity purified from 55 patients with SLE. This compound improved the clinical manifestations of NZBXWXF1 mice in 200 times lower concentration than IVIG. This lupus-specific IVIG was introduced to a peptide phage display library (C-7mer-C). The identified synthetic peptides (idiotype mimetics) were synthesized and used to replace the human anti-dsDNA idiotypes column. IVIG affinity purified on the synthetic peptides columns were determined as peptide-specific IVIG (psIVIG). The psIVIG compound was tested for specificity by ELISA and competition assays.

Each psIVIG inhibited the binding of anti-dsDNA antibodies from 12 lupus patients, to dsDNA, differentially by 15% up to 46% or as a mix up to 87–94%. Naïve mice immunized with a branched peptide composed of the synthetic mimetics of anti-dsDNA idiotypes induced the generation of elevated titers of anti-dsDNA. The anti-dsDNA generation was inhibited in the branced peptide immunized mice, following treatment with psIVIG. A cocktail of psIVIG was introduced to NZBxWxF1. The following clinical parameters were improved in the NZBxWxF1 psIVIG subjected mice: circulating anti-dsDNA antibodies, leukopenia, proteinuria and immunoglobulin deposits in the kidneys.

We introduce herein an IVIG subfraction, specific for anti-dsDNA treatment for lupus patients, and discuss its efficacy and beneficial effect in suppression of humoral and clinical signs of SLE versus regular IVIG.

Affiliations

1. The Center for Autoimmune Diseases, Department of Medicine 'B', Sheba Medical Center, Tel-Hashomer, Israel

   • M Blank
   • , L Slutzki
   •  & Y Shoenfeld

2. OMRIX Biopharmaceuticls Inc., Nes-Ziona, Israel

   • I Nur
   • , R Meidler
   •  & L Bar

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