Background Human Endogenous Retroviruses (HERVs) are ancient retroviral integrations fixed in the genome of humans. As for all retroviruses, HERVs contain three protein coding genes: gag, pol and env. The retroviral envelope proteins can influence human biology through their inherent immune suppressive activity (1) localized to a secondary protein structure (the ISU domain) in the envelope protein.
Our previous research has shown that the env-59-protein of HERV-H is negatively correlated to the inflammatory marker IL-6 in SLE patients, and has an inhibitory effect on stimulated PBMC's from both RA and SLE patients. We aimed to investigate, if this effect could be translated from in vitro to in vivo experiments.
Objectives To examine the anti-inflammatory potential of a peptide based on the ISU domain of HERV-H ENV-59 in the SKG mouse model (2).
Methods At 7–11 weeks of age, female SKG mice were randomized to treatment groups. Arthritis was induced with mannan. After disease induction, the animals were treated daily with subcutaneous injections of a synthetically developed peptide (Env59-ISU), a scrambled peptide or saline. Two 4-week studies were performed. In study one, we wished to demonstrate an anti-inflammatory effect of Env59 ISU. Three groups of 5 mice were tested (group #1: 4 μg peptide/day, group #2:40 μg peptide/day, group #3: saline).
Study two aimed to confirm the results of study one. Forty mice were randomized to 5 treatment groups (group 1: saline, group 2: 1μg/peptide/day, group 3: 4μg/peptide/day, group 4: 20 μg/peptide/day and group 5: 4 μg/scrambled-peptide/day). SKG arthritis was assessed and scoring was performed independently by two persons and blinded to treatment group.
Hind paws from two mice were fixated in 70% ethanol, and subsequently embedded undecalcified in methylmethacrylate. Tissue sections were stained with Masson-Golden trichrome.
Results In study one, we found significantly lower arthritis score in Env59-treated mice compared to those treated with saline. Group #3 receiving 4μg peptide had the lowest average arthritis score throughout the trial (Fig.1), which was confirmed by study two showing, that the 4μg peptide- treated group (group 3) had significantly lower arthritis score compared to saline and the scrambled peptide. The pattern observed in the arthritis score was confirmed using serum amyloid A3 (SAA3) as a biomarker for inflammation and using histology in mice treated with saline compared to peptide-treated mice.
Conclusions We demonstrate that a synthetic peptide corresponding to the sequence of Env59-ISU has anti-inflammatory effect in a chronic inflammatory mouse model of RA and propose the peptide as a potential new treatment for inflammatory diseases.
Tolstrup M et al. Anti-inflammatory effect of a retrovirus-derived immunosuppressive peptide in mouse models. BMC Immunol. 2013;14:51
Sakaguchi N et al. Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice. Nature. 2003 Nov 27;426(6965):454–60.
Disclosure of Interest None declared