New therapeutic strategy against peritoneal sclerosis using gene-modified macrophages

使用基因修饰巨噬细胞对抗腹膜硬化的新治疗策略

• 批准号: 18590893
• 负责人: MIYAZAKI Masanobu
• 金额: $ 2.45万
• 依托单位: Nagasaki University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590893/
• 关键词: peritoneal sclerosis; macrophage; cationized gelatin; HGF

Peritoneal sclerosis is one of the serious complications among the patients with peritoneal dialysis and it prevents long-term peritoneal dialysis therapy. However, the pathogenesis of peritoneal sclerosis remains unknown. In pathological examination, accumulation of macrophages is observed in some patients with peritoneal sclerosis and experimental peritoneal sclerosis model. In this study, we examined an important role of macrophages during the development of peritoneal sclerosis and we tried whether the development of peritoneal sclerosis can be prevented using gene-modified macrophages.It is well known that macrophages infiltrate into inflamed tissue via adhesion molecule and that ICAM-1 is known as one of important adhesion molecules in macrophage infiltration. Firstly, we studied a role of macrophages during the course of peritoneal sclerosis, using ICAM-1(intracellular adhesion molecule)knockout mice using experimental peritoneal sclerosis model with chlorhexidine gluconate. Com … More paring with wild type, ICAM-1 knockout model, macrophage was hardly observed in peritoneal tissue and submesothelial tissue thickening was significantly suppressed From the results, accumulated macrophages in thickened submesothelial tissue plays an important role in development of peritoneal sclerosis.Secondly, gene-modified macrophages were made using cationized gelatin(kindly gifted from Professor Yasuhiko Tabata in Kyoto University) with hepatic growth factor(HGF) gene, which is known to work as antifibrotic factor. We fried to utilize macrophages as a vehicle to express and deliver HGF gene at the peritoneum because macrophages have phagocytotic activity and are capable of migrating to inflamed sites. Intravenous transfer of macrophages carrying HGF expression vector significantly suppressed the submesothelial thickening and reduced collagen III expression in chlorhexidine treated mice.In conclusion, macrophages have a central role of pathogenesis of peritoneal sclerosis and gene-modified macrophages with cationized gelatin including HGF gene may open a new therapeutic strategy against peritoneal sclerosis. Further studies are necessary for applying this method in the patients with peritoneal dialysis as tool of preventing and inhibiting peritoneal sclerosis. Less

腹膜硬化症是腹膜透析患者的严重并发症之一，它阻碍了腹膜透析的长期治疗。然而，腹膜硬化的发病机制仍不清楚。病理检查部分腹膜硬化患者及实验性腹膜硬化模型中可见巨噬细胞聚集。在这项研究中，我们研究了巨噬细胞在腹膜硬化发展过程中的重要作用，并尝试了是否可以使用基因修饰的巨噬细胞来预防腹膜硬化的发展。众所周知，巨噬细胞通过粘附分子浸润到炎症组织中，而ICAM-1被认为是巨噬细胞浸润的重要粘附分子之一。首先，我们研究了巨噬细胞在腹膜硬化过程中的作用，使用ICAM-1（细胞内粘附分子）基因敲除小鼠使用实验性腹膜硬化模型与葡萄糖酸氯己定。网 ...更多信息 与野生型、ICAM-1敲除模型相比，在腹膜组织中几乎没有观察到巨噬细胞，并且中皮下组织增厚被显著抑制。从结果来看，在增厚的中皮下组织中积累的巨噬细胞在腹膜硬化的发展中起重要作用。其次，基因修饰的巨噬细胞用阳离子化明胶制成（由京都大学Yasuhiko Tabata教授赠送），具有肝生长因子（HGF）基因，已知其作为抗纤维化因子起作用。由于巨噬细胞具有吞噬活性并能够迁移到炎症部位，因此我们利用巨噬细胞作为载体在腹膜表达和递送HGF基因。腹腔注射携带HGF表达载体的巨噬细胞可显著抑制氯己定处理小鼠的中膜下增厚和胶原III的表达。结论：巨噬细胞在腹膜硬化的发病机制中起着重要作用，携带HGF基因的阳离子明胶修饰巨噬细胞可能为腹膜硬化的治疗开辟新的途径。将此方法应用于腹膜透析患者，作为预防和抑制腹膜硬化的工具，还需要进一步的研究。少

项目成果

Mizoribine induces remission of relapsed ANCA-associated renal vaculitis.

Mizoribine 可诱导复发性 ANCA 相关肾血管炎的缓解。

• 发表时间: 2006
• 期刊: Nephrology Dialysis Transplantation 21(4)
• 作者: Nishioka Y;Horita Y;Tadokoro M;Taura K;Suyama N;Miyazaki M;Harada T;Kohno S
• 通讯作者: Kohno S

Involvement of leptin in development of fibrosis in mice experimental model of eritoneal dialysis

瘦素参与小鼠腹膜透析实验模型纤维化的发生

• 发表时间: 2006
• 作者: Nakazawa;M.;Abe;K.;Miyazaki;M.;et. al.
• 通讯作者: et. al.

Japanese extraneal collaborated study group:Effects of icodextrin on glycemic and lipid profiles in diabetic patients undergoing peritoneal dialysis.

日本体外合作研究小组：艾考糊精对接受腹膜透析的糖尿病患者血糖和血脂的影响。

• 发表时间: 2007
• 期刊: Am J Nephrol 27
• 作者: Babazono T;Nakamoto H;Kasai K;Kuriyama S;Suginoto T;Nakayama M;Hamada T;Furuya R;Hasegawa H;Kasahara M;Moriishi M;Miyazaki M;Sato M;Yorioka N;Kawaguchi Y
• 通讯作者: Kawaguchi Y

Mizoribine induces remission of relapsed ANCA-associated renal vasculitis

米佐立宾诱导复发性 ANCA 相关肾血管炎的缓解

• 发表时间: 2006
• 期刊: Nephrol Dial Transplant 21
• 作者: Nishioka;Y.;Horita;Y.;Tadokoro;M.;Taura;K.;Suyama;N.;Miyazaki;M.;Harada;T.;Kohno;S
• 通讯作者: S

Expression of KLF5 in experimental peritoneal fibrosis model and anti-fibrotic effect of AM80, an inhibitor of KLF5

KLF5在实验性腹膜纤维化模型中的表达及KLF5抑制剂AM80的抗纤维化作用

• 发表时间: 2006
• 作者: Nakazawa;Y.;Abe;K.;Miyazaki;M.;et. al.
• 通讯作者: et. al.