Pathogenecity of autoantibody in bullous pemphigoid and development of epitope-decoy therapy

大疱性类天疱疮自身抗体的致病性及表位诱饵疗法的进展

基本信息

批准号：
18390309
负责人：
SAWAMURA Daisuke
金额：
$ 11.35万
依托单位：
Hirosaki University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
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-18390309/
关键词：
pemphigoid knockout mouse transgenic mouse epitope decoy BP180 typeXVII collagen gene therapy 水疱性天疱瘡

项目摘要

Bullous pemphigoid (BP) is an autoimmune skin disease characterized by painful erosions and blisters arising on the skin and mucous membrane, and demonstrates distinctive subepidermal clefting histologically. The patients have lgG autoantibody that reacts 180-kD BP antigens in basement membrane zone. Previous passive transfer experiments with lgG from BP patients into animals fails reproducing disease due to the epitope differences between human and recipients. To overcome the species difference between autoantibody and autoantigen, we developed novel approach. We first generated knockout mouse of the BP180 gene, which revealed blister formation as found in human ortholog knockout, non-Herliz junctional epidermolysis bullosa (EB). Next, transgenic rescue experiment using human BP180 cDNA transgene was performed, which resulted in correction of abnormal phenotypes of the knockout mice. Successful transgenic rescue of BP180 KO mice also provides a great promise to gene therapy of EB. These rescued mice with humanized BP180 succeeded in blister formation when lgG from BP patients were passively transferred. Furthermore, treatment with 70 mer recombinant antigenic peptide prevented blister formation significantly. This study first demonstrated direct evidence of BP antibody pathogenicity and feasibility of epitope decoy therapy in BP, and also showed promising effectiveness of corrective gene therapy of EB.

大疱性类天疱疮（BP）是一种自身免疫性皮肤病，其特征是皮肤和粘膜上出现疼痛性糜烂和水疱，并在组织学上表现出独特的表皮下裂隙。患者具有与基底膜区 180-kD BP 抗原发生反应的 IgG 自身抗体。由于人和接受者之间的表位差异，之前使用 BP 患者的 IgG 被动转移到动物体内的实验未能重现疾病。为了克服自身抗体和自身抗原之间的物种差异，我们开发了新的方法。我们首先培育了 BP180 基因的敲除小鼠，该小鼠揭示了在人类直系同源基因敲除非 Herliz 交界性大疱性表皮松解症 (EB) 中发现的水疱形成。接下来，使用人类BP180 cDNA转基因进行转基因拯救实验，结果纠正了基因敲除小鼠的异常表型。 BP180 KO小鼠转基因拯救的成功也为EB的基因治疗提供了广阔的前景。当来自 BP 患者的 IgG 被被动转移时，这些被拯救的带有人源化 BP180 的小鼠成功形成了水泡。此外，用70聚体重组抗原肽处理可显着防止水泡形成。这项研究首次证明了 BP 抗体致病性的直接证据以及表位诱饵疗法在 BP 中的可行性，并且还显示了 EB 纠正基因治疗的有希望的有效性。

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Analysis of the COL17A1 in non-Herlitz junctional epidermolysis bullosa and amelogenesis imperfecta.

DOI：
10.3892/ijmm.18.2.333
发表时间：
2006-08
期刊：
International journal of molecular medicine
影响因子：
5.4
作者：
Hiroyuki Nakamura;D. Sawamura;Maki Goto;Hideki Nakamura;M. Kida;T. Ariga;Y. Sakiyama;K. Tomizawa-
通讯作者：
Hiroyuki Nakamura;D. Sawamura;Maki Goto;Hideki Nakamura;M. Kida;T. Ariga;Y. Sakiyama;K. Tomizawa-

Small-Diameter Porous Poly (epsilon-Caprolactone) Films Enhance Adhesion and Growth of Human Cultured Epidermal Keratinocyte and Dermal Fibroblast Cells.

小直径多孔聚（ε-己内酯）薄膜增强人类培养的表皮角质形成细胞和真皮成纤维细胞的粘附和生长。