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B cell depletion therapy for the model mouse of scleroderma

硬皮病模型小鼠的 B 细胞耗竭疗法

基本信息

批准号：
18591238
负责人：
HASEGAWA Minoru
金额：
$ 2.55万
依托单位：
Kanazawa 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-18591238/
关键词：
Tight skin mouse systemic sclerosis B cell CD20 aintbody-therapy cytokine fibrosis autoimmunity 自己抗体

项目摘要

Systemic sclerosis (scleroderma) is an autoimmune disease characterized by excessive extracellular matrix deposition in the skin. Although autoantibody production correlates with skin sclerosis, a direct role for B lymphocytes in disease development or progression has remained controversial. To address this issue, skin sclerosis and autoimmunity was assessed in tight-skin mice, a genetic model of human systemic sclerosis, following circulating and tissue B cell depletion using an anti-mouse CD20 mAb before and after disease development. CD20 mAb treatment (10-20 rig) depleted the majority (85-99%) of circulating and tissue B cells in newborn and adult tight-skin mice. Dose-dependent B cell depletion in newborn tight-skin mice significantly suppressed (-43%) the development of skin fibrosis and hypergammaglobulinemia, and abrogated rheumatoid factor and autoantibody production. B cell depletion in young tight-skin mice also restored a more normal balance between Th1 and Th2 cytokine mRNA expression in the skin and spleen. By contrast, effective B cell depletion did not affect skin fibrosis, hypergammaglobulinemia, rheumatoid factor and autoantibody levels in adult mice with established disease. Thereby, B cell depletion during disease onset suppressed skin fibrosis, indicating that B cells contribute to the initiation of systemic sclerosis pathogenesis in tight-skin mice but are not required for disease maintenance.

系统性硬化症(硬皮病)是一种自身免疫性疾病，其特征是皮肤中细胞外基质过度沉积。虽然自身抗体的产生与皮肤硬化有关，但B淋巴细胞在疾病发展或进展中的直接作用仍存在争议。为了解决这个问题，在紧皮鼠中评估了皮肤硬化和自身免疫，紧皮鼠是人类系统性硬化症的遗传模型，在疾病发展之前和之后，使用抗鼠CD20单抗对循环和组织B细胞耗尽后的皮肤硬化和自身免疫进行了评估。CD20单抗治疗(10-20Rig)耗尽了新生和成年紧致皮肤小鼠的大部分(85-99%)循环和组织B细胞。新生的紧肤小鼠的B细胞剂量依赖性去除显著抑制了皮肤纤维化和高丙球蛋白血症的发展(-43%)，并消除了类风湿因子和自身抗体的产生。皮肤紧致的年轻小鼠的B细胞枯竭也恢复了皮肤和脾中Th1和Th2细胞因子mRNA表达的更正常平衡。相比之下，有效的B细胞去除并不影响已确诊疾病的成年小鼠的皮肤纤维化、高丙种球蛋白血症、类风湿因子和自身抗体水平。因此，在疾病发生过程中B细胞的耗尽抑制了皮肤纤维化，表明B细胞在紧肤型小鼠系统性硬化症发病机制的启动中起到了作用，但不是疾病维持所必需的。