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Development of novel mouse model for autoimmune diseases using autoantigen knockout mice

使用自身抗原敲除小鼠开发新型自身免疫性疾病小鼠模型

基本信息

批准号：
10470189
负责人：
NISHIKAWA Takeji
金额：
$ 9.66万
依托单位：
Keio 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 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10470189/
关键词：
Autoimmune diseases Pemphigus Animal model Desmoglein Tolerance Autoantibody B cell Knochout mouse

项目摘要

The development of experimental models of active autoimmune diseases can be difficult due to tolerance of autoantigens. Knockout mice do not acquire tolerance of the defective gene product. Using knockout mice lacking desmoglein 3 (Dsg3), the target antigen of pemphigus vulgaris (PV), we established a method to generate an active disease model for this autoantibody-mediated disease. Dsg3ィイD1-/-ィエD1 mice, but not Dsg3ィイD1+/-ィエD1 littermates, produced anti-Dsg3 IgG that was able to bind the native Dsg3 when immunized with recombinant mouse Dsg3. Splenocytes from the immunized Dsg3ィイD1-/-ィエD1 mice were then adoptively transferred into Rag-2ィイD1-/-ィエD1 immunodeficient mice expressing Dsg3. Anti-Dsg3 IgG was stably produced in the recipient mice for over 6 months without further boosting. This IgG bound to Dsg3 in vivo and disrupted the cell-cell adhesion of keratinocytes. Consequently, the recipient mice developed erosions in their oral mucous membranes with typical histologic findings of PV. In addition, the recipient mice showed telogen hair loss, as found in Dsg3ィイD1-/-ィエD1 mice. Collectively, the recipient mice developed the phenotype of PV due to the pathogenic anti-Dsg3 IgG. This model will be valuable for developing novel therapeutic strategies. Furthermore, our approach can be applied broadly for the development of various autoimmune disease models.

由于自身抗原的耐受性，活动性自身免疫性疾病的实验模型的发展可能是困难的。敲除小鼠不能获得对缺陷基因产物的耐受性。我们利用缺乏寻常型天疱疮（pemphigus vulgaris， PV）靶抗原desmoglin 3 （Dsg3）的敲除小鼠，建立了一种产生这种自身抗体介导疾病的活动性疾病模型的方法。Dsg3ィイD1 - / -ィエD1老鼠,但不是Dsg3ィイD1 + / -ィエD1的同胞,anti-Dsg3产生免疫球蛋白,能结合本地Dsg3接种重组时鼠标Dsg3。将免疫后的Dsg3 γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ。抗dsg3 IgG在受体小鼠体内稳定产生超过6个月，没有进一步增加。这种IgG在体内与Dsg3结合，破坏了角质形成细胞的细胞间粘附。因此，受体小鼠的口腔粘膜出现糜烂，具有典型的PV组织学表现。此外，受体小鼠出现休止期脱发，如在Dsg3 γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ。总的来说，受体小鼠由于致病性抗dsg3 IgG而出现PV表型。该模型将对开发新的治疗策略有价值。此外，我们的方法可以广泛应用于各种自身免疫性疾病模型的开发。