GV1001 immunotherapy ameliorates joint inflammation in a murine model of rheumatoid arthritis by modifying collagen-specific T-cell responses and downregulating antigen-presenting cells

•This is the first report on the mechanism and therapeutic effects of GV1001 using in vivo and in vitro models of RA.•GV1001 reduced clinical and histological joint scores in the murine model of rheumatoid arthritis. Also, GV1001 lowered collagen-stimulated IFN-γ and IL-6 production of murine T-cells and reduced TNF-α and IL-6 production in human macrophages in vitro.•The therapeutic effects of GV1001 in the in vivo and in vitro models of rheumatoid arthritis are shown to be the result of modified T-cell reactions that trigger autoantigen and reduce macrophage cytokine production.

This study investigated whether GV1001 may be useful for treating rheumatoid arthritis (RA). Two collagen-induced arthritis (CIA) experiments showed that therapeutic, but not preventive, GV1001 treatment reduced the severity of joint inflammation in CIA. The third CIA experiment indicated that, compared to vehicle treatment, therapeutic GV1001 treatment was associated with a significantly smaller area under the curve for the overall clinical joint score over the 98 day observation period (p < 0.05). GV1001 treatment was also associated with lower Day 98 serum IL-6 levels (p < 0.01) and histological joint scores (p < 0.05). Moreover, splenocytes harvested from the GV1001-treated mice exhibited lower basal and collagen-stimulated production of IFN-γ and IL-6 on Days 49 and 98 than the splenocytes from vehicle-treated mice. The fourth and fifth experiments indicated that earlier treatment resulted in a better response.In addition, human (THP-1) and murine (RAW 264.7) macrophages and fibroblast-like synoviocytes (FLS) from RA patients were used for in vitro analyses. GV1001 treatment of lipopolysaccharide-stimulated macrophages derived from THP-1 and RAW 264.7 monocytes significantly reduced TNF-α and IL-6 secretion (THP-1: all p < 0.05; RAW 264.7: all p < 0.01). However, GV1001 treatment did not affect IL-6 expression in TNFα-stimulated RA FLS.GV1001 reduced the clinical joint scores, serum IL-6 levels, and histological joint scores of mice with CIA. In addition, GV1001 lowered the collagen-stimulated IFN-γ and IL-6 production of murine T-cells and reduced the TNF-α and IL-6 production of macrophages in vitro. Thus, GV1001 may ameliorate joint inflammation by modifying T-cell reactions to the triggering autoantigen and by reducing macrophage cytokine production.

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