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Abstract Number: 3001

Targeting IL-6 By Both Passive or Active Immunization Strategies Prevents Inflammation-Driven Skin Fibrosis

Jerome Avouac1, Lucille Desallais2, Maxime Fréchet3, Muriel Elhai3, Jean François Zagury2 and Yannick Allanore1, 1Paris Descartes University, Rheumatology A Department and INSERM U1016, Cochin Hospital, Paris, France, 2Chaire de Bioinformatique, Laboratoire Génomique, Bioinformatique et Applications, EA 4627, Conservatoire National des Arts et Métiers, Paris, France, 3INSERM U1016, Cochin Institute, Paris, France

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: IL-6, mouse model and systemic sclerosis

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Session Information

Session Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud's - Pathogenesis, Animal Models and Genetics II

Session Type: Abstract Submissions (ACR)

Background/Purpose: Interleukin 6 (IL-6) is a pleiotropic cytokine involved in inflammatory and autoimmune processes. Preliminary data have suggested that IL-6 might contribute to systemic sclerosis (SSc). Our aims were to investigate i) IL6 expression in SSc patients ii) 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 ELISA and immunohistochemistry, respectively. We evaluated the monoclonal IL-6R antibody MR16-1 in the mouse model of bleomycin-induced dermal fibrosis, reflecting early and inflammatory stages of SSc. Six-week-old DBA/2 mice received in parallel subcutaneous injections bleomycin (0,5 mg/ml) and intraperitoneal (ip.) injection of MR16-1 or control antibody at a dose of 2 mg at day 0 followed by one ip. injection of 1 mg at day 7 and 14. Then, we assessed the merit of MR-16 in the tight skin (Tsk-1) mice, an inflammation-independent mouse model of skin fibrosis. Tsk-1 mice received a first ip. injection of 2 mg of MR16-1 or control antibody at the age of 5 weeks followed by one ip. injection of 1 mg once a week for 5 weeks. Thereafter, because of the drawbacks of anti-cytokine monoclonal antibodies, we developed an innovative strategy using active immunization against a small peptide derived from murine IL-6, which was performed in the mouse model of bleomycin-induced dermal fibrosis. 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. Passive immunization with MR16-1 exerted antifibrotic effects in the mouse model of bleomycin-induced dermal fibrosis: dermal thickness, hydroxyproline content and myofibroblast counts were reduced by 25±4% (P=0.02), 30±6% (P=0.007) and 45±7% (P=0.005) respectively, compared to mice receiving control antibody. MR16-1 demonstrated no efficacy in Tsk-1 mice. Mice immunized against the mIS200 peptide derived from murine IL-6 exhibited in the bleomycin mouse model similar antifibrotic effects as passive immunization. We observed a significant reduction of dermal thickness by 20±3% (P=0.02), hydroxyproline content by 25±4% (P=0.005) and myofibroblast counts by 41±9% (P=0.01), compared to the group immunized against the carrier protein alone. 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 the anti-IL-6 active immunization.

Conclusion: 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 or 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 seducing alternative to passive immunization.


Disclosure:

J. Avouac,
None;

L. Desallais,
None;

M. Fréchet,
None;

M. Elhai,
None;

J. F. Zagury,
None;

Y. Allanore,
None.

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