Targeting IL-6 by both passive or active immunization strategies prevents bleomycin-induced skin fibrosis.
Targeting IL-6 by both passive or active immunization strategies prevents bleomycin-induced skin fibrosis.
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DOI：
10.1186/ar4672
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发表时间：
2014-07-24
影响因子：
4.9
通讯作者：
Allanore Y
中科院分区：
文献类型：
--
作者：
Desallais L;Avouac J;Fréchet M;Elhai M;Ratsimandresy R;Montes M;Mouhsine H;Do H;Zagury JF;Allanore Y
白细胞介素-6（IL-6）是一种多效性细胞因子，初步数据表明它可能有助于系统性硬化症（SSc）。我们的目的是调查，首先，IL-6的表达与SSc患者，其次，被动和主动免疫IL-6的疗效，以减少皮肤纤维化的SSc互补小鼠模型。分别采用酶联免疫吸附试验和免疫组织化学方法测定人血清和皮肤中IL-6的表达水平。我们首先在博来霉素诱导的皮肤纤维化小鼠模型中评估了单克隆抗IL-6 R抗体MR 16 -1的抗纤维化特性，反映了SSc的早期和炎症阶段。然后，我们评估了MR 16 -1在紧皮肤-1（Tsk-1）小鼠（一种非炎症依赖性皮肤纤维化模型）中的疗效。此外，我们还开发了一种创新策略，使用基于抗IL-6肽的主动免疫。对浸润的白细胞、T细胞和B细胞进行定量，并测量被动或主动免疫后小鼠血清和皮损皮肤中的IL-6水平。早期SSc患者血清和皮肤IL-6水平显著升高。在博来霉素小鼠模型中，用MR 16 -1处理导致真皮厚度和羟脯氨酸含量分别减少25%（P = 0.02）和30%（P = 0.007）。MR 16 -1在Tsk-1小鼠中没有表现出疗效。此后，针对源自鼠IL-6的小肽免疫小鼠，并且该策略在博来霉素模型中导致真皮厚度和羟脯氨酸含量分别降低20%（P = 0.02）和25%（P = 0.005）。被动和主动免疫导致博莱霉素攻击小鼠皮损皮肤中T细胞浸润减少。在博来霉素注射后，血清和皮肤IL-6水平在用MR 16 -1处理后增加，并且在抗IL-6主动免疫后显著降低。我们的研究结果支持靶向IL-6在早期SSc患者中的相关性，因为IL-6在疾病的早期阶段过表达。通过被动和主动免疫策略靶向IL-6可预防小鼠中博来霉素诱导的真皮纤维化的发展。我们的研究结果突出了针对IL-6的主动免疫的治疗潜力，这是被动免疫的诱人替代方案。
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. 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. 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. 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.
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影响因子：
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作者：
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