A fructosylated peptide derived from a collagen II T cell epitope for long-term treatment of arthritis (FIA-CIA) in mice

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.

Significance of Type II Collagen Posttranslational Modifications: From Autoantigenesis to Improved Diagnosis and Treatment of Rheumatoid Arthritis

“…However, the collagen peptides used in these experiments were not glycosylated and the reported effects were weaker compared to the results with glycosylated peptides, thus strengthening the importance of K264 posttranslational modification. This hypothesis is supported by more recent investigations that displayed the long-term amelioration of arthritis symptoms in mice following the therapeutic intravenous administration of fructosylated at K264 peptides derived from bovine COL2 [181]. Although, the sugar residue attached to K264 is slightly different in these experiments, the obtained results strongly support the general role of glycosylation as an important PTM of the T-cell immunodominant epitope from COL2 with potential for the development of new therapeutic approaches for RA.…”

Hypertonic saline- and detergent-accelerated EDTA-based decalcification better preserves mRNA of bones

“…Inflammation is the most common sign in joint diseases and immunological detection for inflammatory cells is often used for evaluation of the severity of the diseases in the laboratory. To develop arthritis, male DBA/1 mice, 8 weeks in age, were immunized and boosted with bovine collagen II and human fibrinogen as previously reported 36 . After 12 weeks of immunization, the left hind paws, which weighed over 0.180 g (0.144–0.151 g of the native mice at the corresponding age, see Table S1 ), were randomly objected to decalcification either with 15% EDTA (RT) for 1 week or 26% EDTA-plus (45 °C) for 24 h as described.…”

“…For assessment of morphological details following the decalcification, 12 right hind paws of C57 BL76J male mice, ranging 8.5—10 weeks in age, were randomly divided into two groups with 6 paws each (see Table S1 ). For the estimation of antigenicity preservation (see Table S1 ) after decalcification, we selected 12 left hind paws over 0.18 g in weight, from 20-week-old DBA/1 mice which had been immunized and boosted with bovine collagen II and human fibrinogen 36 . The 12 immunized paws were randomly and equally divided into two groups.…”

Reestablish immune tolerance in rheumatoid arthritis

“…In another study, the long-term protective effect of peptide 90578, a novel fructosylated peptide derived from the immunodominant T cell epitope of bovine CII (bCII) was studied using a bCII and human fibrinogen (FIA-CIA) immunized arthritis mice (80). Intravenous administration of peptide 90578 could lead to significantly beneficial effects on clinical outcome parameters and arthritis histology scores for 12 weeks, as well as improved survival time (80).…”

“…In another study, the long-term protective effect of peptide 90578, a novel fructosylated peptide derived from the immunodominant T cell epitope of bovine CII (bCII) was studied using a bCII and human fibrinogen (FIA-CIA) immunized arthritis mice (80). Intravenous administration of peptide 90578 could lead to significantly beneficial effects on clinical outcome parameters and arthritis histology scores for 12 weeks, as well as improved survival time (80). Additionally, several studies have demonstrated that co-administration of selfantigen with an immunomodulator (e.g., calcitriol, aryl-hydrocarbon receptor ligands, or NF-kB inhibitors) could improve autoimmunity, whereas free antigen could not (26).…”