Katsume Asao, Saito Hiroyuki, Yamada Yoshiki, Yorozu Keigo, Ueda Otoya, Akamatsu Ken-ichi, Nishimoto Norihiro, Kishimoto Tadamitsu, Yoshizaki Kazuyuki, Ohsugi Yoshiyuki
Department of Medical Science I, School of Health and Sport Sciences, Osaka University, Osaka, Japan.
Cytokine. 2002 Dec 21;20(6):304-11. doi: 10.1006/cyto.2002.2012.
Transgenic mice carrying human IL-6 cDNA fused with a murine major histocompatibility class-I promoter (H-2L(d)) were serially administered with anti-interleukin-6 receptor (IL-6R) monoclonal antibody (mAb), MR16-1, from the age of 4 weeks to estimate its efficacy on a variety of disorders developed in these mice, most of which are similar to the disorders associated with Castleman's disease. In the control mice treated with isotype-matched mAb, a massive and multiple IgG1 plasmacytosis, mesangial proliferative glomerulonephritis, leukocytosis, thrombocytosis, anemia and abnormalities of blood chemical parameters have developed in accordance with the elevation of serum IL-6, and 50% of mice have died of renal failure by 18 weeks of age. In contrast, the treatment with MR16-1 prevented all these symptoms and prolonged the lifetime of the majority of the mice. Thus, the constitutive overexpression of IL-6 caused various disorders, and the treatment with anti-IL-6R mAb completely prevented from these symptoms. These results clearly confirm that IL-6 indeed plays an essential role in the pathogenesis of a variety of disorders. Furthermore, anti-IL-6R mAb could provide novel therapy for Castleman's disease and MR16-1 should be a useful tool to estimate therapeutic potential of IL-6 antagonists in a variety of murine models for human disease.
携带与人白细胞介素-6（IL-6）互补DNA（cDNA）融合的小鼠主要组织相容性I类启动子（H-2L(d)）的转基因小鼠，从4周龄开始连续给予抗白细胞介素-6受体（IL-6R）单克隆抗体（mAb）MR16-1，以评估其对这些小鼠发生的多种病症的疗效，其中大多数病症与卡斯特曼病相关的病症相似。在用同型匹配mAb治疗的对照小鼠中，随着血清IL-6升高，出现了大量多发性IgG1浆细胞增多、系膜增生性肾小球肾炎、白细胞增多、血小板增多、贫血和血液化学参数异常，到18周龄时50%的小鼠死于肾衰竭。相比之下，用MR16-1治疗可预防所有这些症状，并延长了大多数小鼠的寿命。因此，IL-6的组成型过表达导致了各种病症，而用抗IL-6R mAb治疗可完全预防这些症状。这些结果清楚地证实IL-6确实在多种病症的发病机制中起重要作用。此外，抗IL-6R mAb可为卡斯特曼病提供新的治疗方法，而MR16-1应是评估IL-6拮抗剂在多种人类疾病小鼠模型中治疗潜力的有用工具。
