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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ACR Meeting Abstracts - https://acrabstracts.org/abstract/targeting-il-6-by-both-passive-or-active-immunization-strategies-prevents-inflammation-driven-skin-fibrosis/