Targeting IL-6 by both passive or active immunization strategies prevents bleomycin-induced skin fibrosis

作者：Lucille Desallais, Jérôme Avouac, Maxime Fréchet, Muriel Elhaï, Rojo Ratsimandresy, Matthieu Montès, Hadley Mouhsine, Hervé Do, Jean-François Zagury, Yannick Allanore · 发表于：Arthritis Research & Therapy · 年份：2014 · DOI：10.1186/ar4672 · 被引用次数：78 · 研究领域：Systemic Sclerosis and Related Diseases、Connective Tissue Growth Factor Research、Dermatologic Treatments and Research

INTRODUCTION: Interleukin-6 (IL-6) is a pleiotropic cytokine for which preliminary data have suggested that it might contribute to systemic sclerosis (SSc). Our aims were to investigate, firstly, IL-6 expression in patients with SSc and, secondly, the efficacy of both passive and active immunization against IL-6 to reduce skin fibrosis in complementary mouse models of SSc. METHODS: Human serum levels and skin expression of IL-6 were determined by enzyme-linked immunosorbent assay and immunohistochemistry, respectively. We first evaluated the antifibrotic properties of the monoclonal anti-IL-6R antibody, MR16-1, in the bleomycin-induced dermal fibrosis mouse model, reflecting early and inflammatory stages of SSc. Then, we assessed the efficacy of MR16-1 in tight skin-1 (Tsk-1) mice, an inflammation-independent model of skin fibrosis. Additionally, we have developed an innovative strategy using an anti-IL-6 peptide-based active immunization. Infiltrating leukocytes, T cells, and B cells were quantified, and IL-6 levels were measured in the serum and lesional skin of mice after passive or active immunization. RESULTS: Serum and skin levels of IL-6 were significantly increased in patients with early SSc. Treatment with MR16-1 led in the bleomycin mouse model to a 25% (P = 0.02) and 30% (P = 0.007) reduction of dermal thickness and hydroxyproline content, respectively. MR16-1 demonstrated no efficacy in Tsk-1 mice. Thereafter, mice were immunized against a small peptide derived fr...