Neutralizing monoclonal antibody to human connective tissue growth factor ameliorates transforming growth factor-β-induced mouse fibrosis
Neutralizing monoclonal antibody to human connective tissue growth factor ameliorates transforming growth factor-β-induced mouse fibrosis
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DOI：
10.1002/jcp.21449
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发表时间：
2008-09-01
影响因子：
5.6
通讯作者：
Takehara, Kazuhiko
中科院分区：
文献类型：
--
作者：
Ikawa, Yuka;Ng, Poh-Sing;Takehara, Kazuhiko
皮肤纤维化病症如系统性硬化症（SSc）的特征在于细胞外基质（ECM）的过度积累，并且被理解为在纤维化生长因子的影响下发展。为了更好地了解SSc持续性纤维化的详细机制，我们先前建立了由外源性应用生长因子诱导的皮肤纤维化的动物模型。在该模型中，转化生长因子-P（TGF-β）瞬时诱导皮下纤维化，并且在TGF-β后连续注射结缔组织生长因子（CTGF）引起持续性纤维化。这些结果表明，CTGF在持续性皮肤纤维化的发展中起着重要作用，CTGF可能是皮肤纤维化的潜在和特异性的治疗靶点。因此，本研究的目的是开发一种抗人CTGF的中和性单克隆抗体。我们还研究了抗体在我们的动物模型中的中和作用。首先，利用DNA免疫的方法，我们研制了一组能识别人CTGF天然构象的抗CTGF抗体。接下来，为了检查这些抗体的抗纤维化作用，新生B6小鼠接受TGF-β与抗CTGF中和抗体或对照纯化免疫球蛋白的皮下注射3天。与对照组相比，抗CTGF抗体显著降低皮肤纤维化和胶原含量。这些结果表明，我们的抗CTGF抗体能够至少部分阻断皮肤纤维化的发展，并且这些抗CTGF中和抗体可用作治疗皮肤纤维化疾病如SSc的可行策略。
Skin fibrotic disorders such as systemic sclerosis (SSc) are characterized by an excessive accumulation of extracellular matrix (ECM) and are understood to develop under the influence of fibrogenic growth factors. To better understand the detailed mechanisms of persistent fibrosis in SSc, we have previously established an animal model of skin fibrosis induced by exogenous application of growth factors. In this model, transforming growth factor-P (TGF-beta) transiently induced subcutaneous fibrosis and serial injections of connective tissue growth factor (CTGF) after TGF-beta caused persistent fibrosis. These results suggest that CTGF plays an important role in the development of persistent skin fibrosis and that CTGF may be a potential and specific therapeutic target in skin fibrosis. Therefore, the aim of the current study is to develop a neutralizing monoclonal antibody against human CTGF. We also investigated the neutralizing effect of the antibodies in our animal model. Firstly, by using the DNA immunization method, we developed a panel of anti-CTGF antibodies recognizing the native conformation of human CTGF. Next, to examine the anti-fibrosing effects of these antibodies, newborn B6 mice received subcutaneous injections of TGF-beta for 3 days with either anti-CTGF neutralizing antibodies or control purified immunoglobulin. Anti-CTGF antibodies significantly reduced skin fibrosis and collagen contents compared with the control group. These results suggest that our anti-CTGF antibodies are capable of blocking the development of skin fibrosis at least partially and these anti-CTGF neutralizing antibodies may be useful as the feasible strategy to treat skin fibrotic diseases as SSc.