Therapeutic effects of anti-Bone Morphogenetic Protein and Activin Membrane-Bound Inhibitor treatment in psoriasis and arthritis.

OBJECTIVES: Transforming growth factor beta (TGFbeta) inhibitor Bone Morphogenetic Protein and Activin Membrane-Bound Inhibitor (BAMBI) has been shown to control CD4(+) T lymphocytes differentiation into either tolerogenic regulatory T (Tregs) or pathogenic TH 17 cells through the regulation of TGFbeta and IL-2 signaling strength. In the present study, we explore the potential beneficial effects of its pharmacological inhibition with new anti-BAMBI monoclonal antibodies (mAbs) in different skin and joint experimental chronic-inflammatory/autoimmune diseases. METHODS: Development of saccharomyces cerevisiae mannan-induced psoriatic arthritis (MIP) (n= 18-30 mice/group), imiquimod-induced skin psoriasis (n= 20-30 mice/group) or collagen type II-induced arthritis (CIA) (n= 13-16 mice/group) was analyzed in a total number of 2-5 different experiments with B10.RIII wild type (WT) or BAMBI-deficient mice treated or not with B101.37 (mouse IgG1 anti-BAMBI), mouse IgG1 anti-TNP isotype control, anti-CD25 or anti-TGFbeta mAbs. RESULTS: Treatment of normal mice with an IgG1 anti-BAMBI mAb, clone B101.37, expands Tregs in vivo and has both preventive and therapeutic effects in the murine model of MIP (p<0.05 in both cases). Disease protection is mediated by Tregs, which control the activation and expansion of pathogenic IL-17-producing cells, and is dependent on TGFbeta. Furthermore, B101.37 treatment blocks the development of skin psoriasis induced by imiquimod and of CIA (p<0.05 in both cases). Finally, the pharmacological inhibition of BAMBI with the IgM anti-BAMBI B143.14 mAb also potentiates the suppressive activity of Tregs in vitro (p<0.001). CONCLUSIONS: We identify BAMBI as a promising new therapeutic target for chronic-inflammatory diseases and other pathological conditions modulated by Tregs.