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Analysis of the onset mechanisms of Psoriasis Vulgaris using transgenic mice

利用转基因小鼠分析寻常型银屑病的发病机制

基本信息

批准号：
10470188
负责人：
YOSHIKAWA Kunihiko
金额：
$ 8.38万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2000
项目状态：
已结题

项目摘要

Psoriasis is an inflammatory and proliferative disease of the skin. Some evidences indicate that psoriasis is a T-cell mediating autoimmune disease although the pathogenesis is still unclear. To study the onset mechanisms of psoriasis, here we have established transgenic mice.Various cytokines may orchestrate the pathogenesis by controlling the interaction between T cells and keratinoctes. Among them, cytokines of IL6 family activate stat3 pathway. We have provided stat 3 conditional knock out mice (K5-Cre : Stat3^<flox/->) that loose stat 3 in keratinocytes by way of the cre-loxP strategy. These mutant mice have expressed spontaneous ulcers. This phenotype was not due to supressed proliferation but to impaired migration of keratinocytes.Antigens expressed in keratinocytes are presumably targets for the autoimmune response of T cells. Based on this idea, we have established transgenic mice expressing chicken ovalbumin (OVA) as a model antigen under keratin-5 promoter (K5-mOVA). MHC class II promoter-mOVA transgenic (II-mOVA) mice were used as a control. From the experiment with transfer of OVA specific T cells (OT-I) into K5-mOVA, antigens expressed in the epidermis are constitutively presented to T cells in the draining lymph nodes. T cells recognized the antigen, followed by proliferation tha was detected with the CFSE method. T cells carryng green fluorescence protein (GFP) started infiltrating the skin on day 5 after transfer. This migration induced non-specific infiltration of host T cells and acanthosis as well. Some of OVA-specific TCR and K5-mOVA double transgenic mice showed inflammation of the skin and scaling although the incidence was around 5 percent. Now we are providing athymic (nude) K5-mOVA mice having been transplanted with TCR transgenic bone marrow, followed by transplantation with normal irradiated thymus to see whether T cells currently generated from the thymus induce skin diseas or not.

牛皮癣是一种皮肤炎症和增殖性疾病。一些证据表明牛皮癣是一种T细胞介导的自身免疫性疾病，尽管其发病机制尚不清楚。为了研究银屑病的发病机制，我们建立了转基因小鼠。多种细胞因子可能通过控制T细胞和角质细胞之间的相互作用来协调发病机制。其中，IL6家族细胞因子激活stat3通路。我们提供了 stat 3 条件敲除小鼠 (K5-Cre : Stat3^<flox/->)，通过 cre-loxP 策略在角质形成细胞中释放 stat 3。这些突变小鼠表现出自发性溃疡。这种表型并不是由于增殖受到抑制，而是由于角质形成细胞的迁移受损。角质形成细胞中表达的抗原可能是 T 细胞自身免疫反应的靶标。基于这个想法，我们建立了在角蛋白5启动子（K5-mOVA）下表达鸡卵清蛋白（OVA）作为模型抗原的转基因小鼠。 MHC II类启动子-mOVA转基因(II-mOVA)小鼠用作对照。通过将 OVA 特异性 T 细胞 (OT-I) 转移至 K5-mOVA 的实验，表皮中表达的抗原被组成型呈递给引流淋巴结中的 T 细胞。 T 细胞识别抗原，随后增殖，通过 CFSE 方法检测。携带绿色荧光蛋白 (GFP) 的 T 细胞在转移后第 5 天开始渗透皮肤。这种迁移还引起宿主 T 细胞的非特异性浸润和棘皮症。一些OVA特异性TCR和K5-mOVA双转基因小鼠表现出皮肤炎症和鳞屑，尽管发生率约为5%。现在我们提供移植了TCR转基因骨髓的无胸腺（裸）K5-mOVA小鼠，然后移植正常辐照的胸腺，以观察目前从胸腺产生的T细胞是否会诱发皮肤病。