Abstract
Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease which affects primarily the joints. Peptides of several proteins have shown an effect in some experimental animal models of RA. We investigated arthritis development in male DBA/1 mice which were injected with bovine collagen II (bCII) and human fibrinogen (hFib) on days 0 and 21, leading to stable and reproducible disease induction in 100% of immunized mice (FIA-CIA). In a second study, two bCII—derived peptides were given three times in the course of 6 weeks after FIA-CIA induction to test for impact on arthritis. Mice were scored weekly for arthritis and anti-citrullinated peptide antibodies (ACPAs) were determined in the sera taken on days 0, 14, 35, 56 and 84. Histology of the hind paws was performed at the end of the experiment. Intravenous administration of peptide 90578, a novel fructosylated peptide derived from the immunodominant T cell epitope of bCII, at a dosage of 1 mg/kg resulted in significant beneficial effects on clinical outcome parameters and on the arthritis histology scores which was sustained over 12 weeks. Survival tended to be improved in peptide 90578-treated mice. Intravenous administration of pure soluble peptide 90578 without adjuvants is a promising approach to treat RA, with treatment starting at a time when ACPAs are already present. The results complement existing data on peptide “vaccination” of healthy animals, or on treatment using recombinant peptide expressing virus or complex biological compounds.
Highlights
Abbreviations anti-citrullinated peptide antibodies (ACPAs) Anti-citrullinated peptide antibodies adjuvantinduced arthritis (AIA) Adjuvant-induced arthritis bovine collagen II (bCII) Bovine collagen II BSA Bovine serum albumin Complete Freunds Adjuvant (CFA) Complete Freunds adjuvant CCP Cyclic citrullinated peptides disease modifying anti-rheumatic drugs (DMARDs) Disease modifying anti-rheumatic drugs FIA-collagen-induced arthritis (CIA) BCII- and human fibrinogen (hFib)-immunized mice which develop Rheumatoid Arthritis (RA)-like arthritis FMOC Fluorenylmethoxycarbonyl hFib Human fibrinogen incomplete Freunds Adjuvant (IFA) Incomplete Freunds adjuvant IL6R Interleukin-6 receptor MHC II Major histocompatibility complex class II PBS Phosphate-buffered saline RA Rheumatoid arthritis RF Rheumatoid factor TGF-β Transforming growth factor beta TNF Tumour necrosis factor
Therapy of rheumatoid arthritis mainly relies on disease modifying anti-rheumatic drugs (DMARDs) such as the conventional synthetic methotrexate, biological drugs (TNF, T cell, B cell or IL-6R-inhibitors) or the targeted synthetic janus kinase inhibitor tofacitinib
When the peptide was mixed together with collagen at a dose which exceeded the amount of collagen II molecules by 480-fold on a molar basis, this mixture succeeded in completely preventing the development of arthritis in CIA mice[14]
Summary
Abbreviations ACPAs Anti-citrullinated peptide antibodies AIA Adjuvant-induced arthritis bCII Bovine collagen II BSA Bovine serum albumin CFA Complete Freunds adjuvant CCP Cyclic citrullinated peptides DMARDs Disease modifying anti-rheumatic drugs FIA-CIA BCII- and hFib-immunized mice which develop RA-like arthritis FMOC Fluorenylmethoxycarbonyl hFib Human fibrinogen IFA Incomplete Freunds adjuvant IL6R Interleukin-6 receptor MHC II Major histocompatibility complex class II PBS Phosphate-buffered saline RA Rheumatoid arthritis RF Rheumatoid factor TGF-β Transforming growth factor beta TNF Tumour necrosis factor. Coimmunization with CII and of CII-derived peptide 245–270 [s260,261,263] leads to a dose-dependent effect on the incidence of arthritis in the mouse CIA model in DBA/1 mice. Gene therapy with hematopoietic stem cells which had been infected with lentiviral particles expressing the CII 259–270 peptide on MHC-Aq-complex several weeks before the immunization reduced the rate and the severity of CIA in DBA/1 m ice[16]. Since we wanted to study a disease model which should be closer to the condition of human RA patients, we investigated the administration of peptides derived from the immunodominant epitope of CII in CIA without an additional MHC complex in a long-term mouse model of RA when they were given after the induction of arthritis. We investigated the effects of a novel fructosylated modification of the epitope peptide and compared them to those of the non-fructosylated peptide variant
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