Ijima K, Murakami M, Okamoto H, Inobe M, Chikuma S, Saito I, Kanegae Y, Kawaguchi Y, Kitabatake A, Uede T
Division of Molecular Immunology, Institute for Genetic Medicine, Hokkaido University, 060-0815 Sapporo, Japan.
Hum Gene Ther. 2001 Jun 10;12(9):1063-77. doi: 10.1089/104303401750214285.
We previously constructed an adenovirus vector carrying a gene encoding a soluble form of fusion protein, consisting of the extracellular portion of cytotoxic lymphocyte antigen 4 (CTLA4) and the Fc portion of human immunoglobulin G1 (Adex1CACTLA4IgG). Murine type II collagen-induced arthritis (CIA) was treated with Adex1CACTLA4IgG. A single intraarticular injection of 1 x 10(5) PFU was able to support serum CTLA4IgG at more than 10 microg/ml for at least 12 weeks and was able to inhibit the CIA clinically and histologically. In contrast, intravenous, intramuscular, or subcutaneous injection of 1 x 10(5) PFU was unable to support a significant level of serum CTLA4IgG and thus was unable to inhibit the development of arthritis. Thus, we demonstrated that (1) a low-dose intraarticular injection of Adex1CACTLA4IgG was effective in delaying the onset of CIA and reducing the severity of arthritis; (2) an intraarticular (knee joint) injection of Adex1CACTLA4IgG effectively blocked the development of arthritis in distal paws; (3) the inhibitory effect of Adex1CACTLA4IgG lasted at least up to 20 weeks; (4) although serum CTLA4IgG at more than 10 microg/ml persisted for at least 12 weeks, mice treated by intraarticular injection of Adex1CACTLA4IgG were not anergic to adenovirus and were able to mount antibody responses against various antigens.
我们之前构建了一种腺病毒载体，其携带一个编码可溶性融合蛋白的基因，该融合蛋白由细胞毒性淋巴细胞抗原4（CTLA4）的胞外部分和人免疫球蛋白G1的Fc部分组成（Adex1CACTLA4IgG）。用Adex1CACTLA4IgG治疗小鼠II型胶原诱导的关节炎（CIA）。单次关节内注射1×10⁵ 空斑形成单位（PFU）能够使血清CTLA4IgG维持在10微克/毫升以上至少12周，并能够在临床和组织学上抑制CIA。相比之下，静脉内、肌肉内或皮下注射1×10⁵ PFU无法维持显著水平的血清CTLA4IgG，因此无法抑制关节炎的发展。因此，我们证明了：（1）低剂量关节内注射Adex1CACTLA4IgG可有效延迟CIA的发病并减轻关节炎的严重程度；（2）关节内（膝关节）注射Adex1CACTLA4IgG可有效阻断远端爪子关节炎的发展；（3）Adex1CACTLA4IgG的抑制作用至少持续20周；（4）尽管血清CTLA4IgG浓度超过10微克/毫升至少持续12周，但通过关节内注射Adex1CACTLA4IgG治疗的小鼠对腺病毒无反应，并且能够针对各种抗原产生抗体反应。
