Kawaguchi Y
Section of Immunopathogenesis, Hokkaido University, Sapporo, Japan.
Hokkaido Igaku Zasshi. 1999 Nov;74(6):467-75.
We examined whether multiple intraperitoneal injection of a soluble form of a chimeric protein consisting of an extracellular portion of cytotoxic T lymphocyte-associated protein 4 and an Fc portion of human IgG1(CTLA4IgG) at the initiation phase could successfully control the subsequent development of experimental allergic encephalomyelitis (EAE). We demonstrated that CTLA4IgG treatment could delay the onset and reduce the severity of EAE in early phase of disease development. More importantly, CTLA4IgG treatment significantly reduced the incidence of EAE. This was in good agreement to that spleen cells obtained from CTLA4IgG-treated animals responded poorly to myelin basic protein (MBP) in vitro as compared to those from human IgG-treated animals. However, the CTLA4IgG-treated mice eventually developed EAE and after all, incidence of EAE was not significantly different from that in control group. We then tested whether a gene therapy using adenovirus vector containing CTLA4IgG (Adex1CACTLA4IgG) could inhibit the development of EAE. We demonstrated that incidence and severity of EAE were significantly inhibited by a single injection of intravenous Adex1CACTLA4IgG up to 8 months. Thus, this study demonstrated the efficacy of a single dose of adenovirus-mediated gene therapy in controlling EAE as compared to repeated injection of purified CTLA4IgG proteins.
我们研究了在起始阶段多次腹腔注射由细胞毒性T淋巴细胞相关蛋白4的细胞外部分和人IgG1的Fc部分组成的嵌合蛋白的可溶性形式（CTLA4IgG）是否能成功控制实验性自身免疫性脑脊髓炎（EAE）的后续发展。我们证明，CTLA4IgG治疗可延迟疾病发展早期EAE的发病并降低其严重程度。更重要的是，CTLA4IgG治疗显著降低了EAE的发病率。这与以下情况高度一致：与用人IgG治疗的动物相比，从接受CTLA4IgG治疗的动物获得的脾细胞在体外对髓鞘碱性蛋白（MBP）的反应较差。然而，接受CTLA4IgG治疗的小鼠最终还是患上了EAE，毕竟EAE的发病率与对照组没有显著差异。然后，我们测试了使用含有CTLA4IgG的腺病毒载体（Adex1CACTLA4IgG）进行基因治疗是否能抑制EAE的发展。我们证明，单次静脉注射Adex1CACTLA4IgG可显著抑制EAE的发病率和严重程度，长达8个月。因此，本研究证明了与重复注射纯化的CTLA4IgG蛋白相比，单剂量腺病毒介导的基因治疗在控制EAE方面的疗效。
