title: Targeting IL-6 by both passive or active immunization strategies prevents bleomycin-induced skin fibrosis.
abstract: BACKGROUND
  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 from murine IL-6 and this strategy led in the bleomycin model to a 20% (P = 0.02) and 25% (P = 0.005) decrease of dermal thickness and hydroxyproline content, respectively. Passive and active immunization led to decreased T-cell infiltration in the lesional skin of mice challenged with bleomycin. Upon bleomycin injections, serum and skin IL-6 levels were increased after treatment with MR16-1 and were significantly reduced after anti-IL-6 active immunization.
  
  
  CONCLUSIONS
  Our results support the relevance of targeting IL-6 in patients with early SSc since IL-6 is overexpressed in early stages of the disease. Targeting IL-6 by both passive and active immunization strategies prevented the development of bleomycin-induced dermal fibrosis in mice. Our results highlight the therapeutic potential of active immunization against IL-6, which is a seductive alternative to passive immunization.
authors: Lucille
authors: L
authors: Desallais
authors: Jérôme
authors: J
authors: Avouac
authors: Maxime
authors: M
authors: Fréchet
authors: Muriel
authors: M
authors: Elhai
authors: Rojo
authors: R
authors: Ratsimandresy
authors: Matthieu
authors: M
authors: Montes
authors: Hadley
authors: H
authors: Mouhsine
authors: Hervé
authors: H
authors: Do
authors: Jean-François
authors: JF
authors: Zagury
authors: Yannick
authors: Y
authors: Allanore
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001761:Bleomycin / Q000633:toxicity; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005355:Fibrosis / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control; D006801:Humans; D007114:Immunization / Q000379:methods*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008875:Middle Aged; D012595:Scleroderma, Systemic / Q000276:immunology*; D012871:Skin Diseases / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*; D000093242:Interleukin-6 Inhibitors
chemical_list: D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D001761:Bleomycin; D000093242:Interleukin-6 Inhibitors