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Objective: In rheumatoid arthritis (RA), destruction of articular cartilage by the inflamed synovium is considered to be driven by increased activities of proteolytic enzymes, including matrix metalloproteinases (MMPs). The purpose of this study was to investigate the therapeutic potential of selective inhibition of membrane type 1 MMP (MT1-MMP) and its combination with tumor necrosis factor (TNF) blockage in mice with collagen-induced arthritis (CIA)., Methods: CIA was induced in DBA/1 mice by immunization with bovine type II collagen. From the onset of clinical arthritis, mice were treated with MT1-MMP selective inhibitory antibody DX-2400 and/or TNFR-Fc fusion protein. Disease progression was monitored daily, and serum, lymph nodes, and affected paws were collected at the end of the study for cytokine and histologic analyses. For in vitro analysis, bone marrow-derived macrophages were stimulated with lipopolysaccharide for 24 hours in the presence of DX-2400 and/or TNFR-Fc to analyze cytokine production and phenotype., Results: DX-2400 treatment significantly reduced cartilage degradation and disease progression in mice with CIA. Importantly, when combined with TNF blockade, DX-2400 acted synergistically, inducing long-term benefit. DX-2400 also inhibited the up-regulation of interleukin-12 (IL-12)/IL-23 p40 via polarization toward an M2 phenotype in bone marrow-derived macrophages. Increased production of IL-17 induced by anti-TNF, which correlated with an incomplete response to anti-TNF, was abrogated by combined treatment with DX-2400 in CIA., Conclusion: Targeting MT1-MMP provides a potential strategy for joint protection, and its combination with TNF blockade may be particularly beneficial in RA patients with an inadequate response to anti-TNF therapy., (© 2016 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.)

Introduction: The purpose of this study was to determine if oral administration of the interleukin (IL) 12/IL-23 inhibitor, STA-5326, is effective in experimental autoimmune uveoretinitis (EAU)., Methods: C57BL/6J mice were immunised with human interphotoreceptor retinoid binding protein peptide (IRBP 1-20). STA-5326 at a dose of either 5 mg/kg or 20 mg/kg, or vehicle alone, was orally administered once a day for six days a week from day 0 to day 14. Fundus examination was performed on day 14 and day 18 after immunisation. Mice were euthanased on day 18 and the eyes were enucleated for histopathological examination. In vivo-primed draining lymph node cells were stimulated with IRBP 1-20 and culture supernatant was harvested for assay of interferon (IFN)-gamma and IL-17 by ELISA. Intracellular expression of IFN-gamma and IL-17 in CD4+ T cells of cultured draining lymph node cells was assessed by flow cytometry. The level of IL-12 p40 in serum was examined in STA-5326-treated or vehicle-treated mice receiving immunisation., Results: The level of IL-12 p40 in serum was decreased in mice treated with STA-5326. Oral administration of either 5 mg/kg or 20 mg/kg STA-5326 reduced the severity of EAU on day 14 and 18. In addition, mice treated with 20 mg/kg STA-5326 showed significantly decreased severity of EAU by histopathological analysis. Although IFN-gamma production of draining lymph node cells was increased in STA-5326-treated mice by ELISA analysis, the proportion of IFN-gamma-producing cells was not significantly altered. However, IL-17 production and the proportion of IL-17-producing cells were significantly reduced in STA-5326-treated mice. Furthermore, oral administration of STA-5326 during the effector phase reduced the severity of EAU., Conclusions: These results indicate that oral administration of the IL-12/IL-23 inhibitor STA-5326 is effective in suppressing inflammation in the EAU model, and reduces the expansion of IL-17-producing cells. STA-5326 may represent a new therapeutic modality for human refractory uveitis.