Yasuda H, Nagata M, Arisawa K, Yoshida R, Fujihira K, Okamoto N, Moriyama H, Miki M, Saito I, Hamada H, Yokono K, Kasuga M
Second Department of Internal Medicine, Kobe University School of Medicine, Kobe 650-0017, Japan.
J Clin Invest. 1998 Nov 15;102(10):1807-14. doi: 10.1172/JCI2675.
Local production of immunosuppressive cytokines will be one of the most suitable therapeutic strategies against organ-specific autoimmune diabetes. To establish such a new therapy, we constructed recombinant adenoviral vectors with inserted mIL-12p40 (Ad.IL-12p40) and mIL-10 (Ad.IL-10). Sufficient amounts of IL-12p40 and IL-10 were secreted by relevant adenovirus-transfected nonobese diabetic (NOD) islets. Shortly after transfection, 400 NOD islets transfected with Ad.IL-12p40 or Ad.IL-10 were transplanted under the renal capsule of a newly diabetic NOD mouse. NOD mice with IL-12p40-producing islet grafts kept normoglycemia in all of 14 grafted mice for over 4 wk after transplantation. In contrast, NOD mice with IL-10-producing islet grafts became diabetic in all of six grafted mice within 2 wk af-ter transplantation. Reverse transcription-PCR analysis revealed that local production of IL-12p40 led to the decrease of interferon-gamma and the augmentation of transforming growth factor-beta at the graft site. These results suggest that IL-12 plays an important role in the destruction of islet cells at the inflamed site of autoimmunity. Such a local blockade of IL-12 would be a useful gene therapy for human autoimmune diabetes.
局部产生免疫抑制性细胞因子将是针对器官特异性自身免疫性糖尿病的最合适治疗策略之一。为了建立这种新疗法，我们构建了插入小鼠白细胞介素12 p40（Ad.IL - 12p40）和小鼠白细胞介素10（Ad.IL - 10）的重组腺病毒载体。相关腺病毒转染的非肥胖糖尿病（NOD）胰岛分泌了足够量的白细胞介素12 p40和白细胞介素10。转染后不久，将400个用Ad.IL - 12p第40或Ad.IL - 10转染的NOD胰岛移植到新患糖尿病的NOD小鼠的肾包膜下。移植后4周以上，接受产生白细胞介素12 p40的胰岛移植的NOD小鼠在所有14只移植小鼠中均保持血糖正常。相比之下，接受产生白细胞介素10的胰岛移植的NOD小鼠在移植后2周内，所有6只移植小鼠均患糖尿病。逆转录 - PCR分析显示，局部产生白细胞介素- 12p40导致移植部位干扰素-γ减少，转化生长因子-β增加。这些结果表明，白细胞介素12在自身免疫炎症部位的胰岛细胞破坏中起重要作用。这种对白细胞介素12的局部阻断可能是治疗人类自身免疫性糖尿病的一种有用的基因疗法。
