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Responsible proteins and genes for the development of intractable vasculitis

顽固性血管炎发生的相关蛋白质和基因

基本信息

批准号：
07457583
负责人：
KATO Mitsuyasu
金额：
$ 0.77万
依托单位：
The Cancer Institute, Japanese Foundatiion for Cancer Research
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

项目摘要

Systemic vasculitis is a major complication of autoimmune diseases such as SLE and RA.However, it is still unclear whether this complication is a manifestation of advanced disease or represents distinct entities possibly restricted by genetic factors. An MRL/lpr strain of mice is one of the few animal models for systemic vasculitis, conicidentally developing lupus-like nephritis and artheritis. Using this strain, we clarified several responsible proteins and genes for the development and progression of systemic vasculitis as follows. 1. Taking advantage that the hybrid mice with non-vasculitis-prone C3H/lpr mice, (MRL/lprx C3H/lpr) xMRL/lpr, develop vasculitis at random, resulted from the rearrangement of the genetic background of MRL/lpr mice, we clarified that macrophage-relating cytokines have a limited pathogenic role in vasculitis. Moreover, one of these cytokines, Eta-1, had an allelic difference in the nucleotide sequence of the gene transcript between these two strains. 2. A ne … More wly established strain of mice, McH5/lpr, from the hybrid mice, developed severe vasculitis, but not glomerulonephritis and arthritis, indicating that vasculitis is under the control of genes different from those of other autoimmune diseases. Moreover, vasculitis in this strain was not associated with increased anti-DNA antibodies and pANCA.3. We established a novel vasculitis-prone mice with a deficit in the functional Fas ligand, MRL/gld, and succeeded in ameliorating vasculitis by the treatment with anti-Fas antibodies and, moreover, in transfer of vasculitis to normal mice. 4. By using MRL/lprx (MRL/lprx C3H/lpr) F1 mice, we performed the linkage analysis of vasculitis with microsatellite makers to find out vasculitis-susceptible gene loci. 5. Transfer of the interferon regulatory factor-1 gene, IRF-1, to MRL/lpr mice induced the suppression of vasculitis in these mice, indicating that vasculitis is under the control of the background genes regulatable by IRF-1.6. A transgenic mouse strain aberrantly expressing soluble E-selectin was newly established, in which the development of experimental lupusnephritis induced by the monoclonal antibodies derived from MRL/lpr mice was remarkably inhibited. This indicates that E-selectin is a critical molecule inducing microvascular injury in MRL/lpr mice. Less

系统性血管炎是SLE和RA等自身免疫性疾病的主要并发症，但其是否为晚期疾病的表现，还是受遗传因素限制的特殊疾病，目前尚不清楚。小鼠的MRL/lpr品系是系统性血管炎、持续发展的狼疮样肾炎和关节炎的少数动物模型之一。使用该菌株，我们阐明了几个负责系统性血管炎的发展和进展的蛋白质和基因如下。1.利用MRL/lpr小鼠遗传背景重排导致的（MRL/lprx C3 H/lpr）xMRL/lpr小鼠与无血管炎倾向的C3 H/lpr小鼠杂交后随机发生血管炎的特点，阐明了巨噬细胞相关细胞因子在血管炎中的致病作用有限。此外，这些细胞因子之一，Eta-1，在这两种菌株之间的基因转录物的核苷酸序列中具有等位基因差异。2.的ne ...更多信息从杂交小鼠中建立的小鼠品系McH 5/lpr发生了严重的血管炎，但没有肾小球肾炎和关节炎，表明血管炎是在不同于其他自身免疫性疾病的基因的控制下。此外，该品系的血管炎与抗DNA抗体和pANCA增加无关。我们建立了一种新的血管炎倾向的小鼠与缺陷的功能性Fas配体，MRL/gld，并成功地改善血管炎的治疗与抗Fas抗体，而且，在转移到正常小鼠的血管炎。4.利用MRL/lprx（MRL/lprx C3 H/lpr）F1小鼠进行血管炎微卫星标记连锁分析，寻找血管炎易感基因位点。5.转移干扰素调节因子-1基因，IRF-1，MRL/lpr小鼠诱导这些小鼠的血管炎的抑制，表明血管炎是受IRF-1.6调节的背景基因的控制。本文报道了一株异常表达可溶性E-选择素的转基因小鼠，该转基因小鼠对MRL/lpr小鼠单克隆抗体诱发的实验性狼疮肾炎有明显的抑制作用。这表明E-选择素是MRL/lpr小鼠中诱导微血管损伤的关键分子。少