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

全身性血管炎是自身免疫性疾病（例如SLE和RA）的主要并发症。但是，尚不清楚这种并发症是否是晚期疾病的表现还是代表不同的实体可能受遗传因素限制。小鼠的MRL/LPR菌株是为数不多的全身性血管炎动物模型之一，它孔形成了狼疮样肾炎和艺术家。使用这种菌株，我们阐明了几种负责任的蛋白质和基因，用于全身血管炎的发展和进展，如下所示。 1。利用与非血管炎的混合小鼠易受的C3H/LPR小鼠，（MRL/LPRX C3H/LPR）XMRL/LPR随机发展血管炎，这是由于MRL/LPR小鼠的遗传背景重新排列而产生的，我们明确了一种有限的cateTogenical cantenogenication cantogenical cantenogenication。此外，这些细胞因子之一ETA-1在这两种菌株之间的核转录本上存在等位基因差异。 2。杂种小鼠的MCH5/LPR的菌株较高的菌株，患有严重的血管炎，但没有肾小球肾炎和关节炎，这表明血管炎受到与其他自身免疫性疾病不同的基因的控制。此外，这种菌株中的血管炎与抗DNA抗体和panca.3无关。我们建立了一只易于血管炎的新型小鼠，在功能性FAS配体，MRL/GLD中存在缺陷，并通过抗FAS抗体的治疗成功地改善了血管炎，此外，还将血管炎转移到正常小鼠中。 4。通过使用MRL/LPRX（MRL/LPRX C3H/LPR）F1小鼠，我们与微卫生间制造商进行了血管炎的连锁分析，以发现具有血管炎的基因基因座。 5。将干扰素调节因子-1基因IRF-1转移至MRL/LPR小鼠诱导这些小鼠的血管炎抑制，这表明血管炎受IRF-1.6调节的背景基因的控制。新近建立了异常表达固体E-选择蛋白的转基因小鼠菌株，其中源自MRL/LPR小鼠的单克隆抗体诱导的实验性狼疮性炎的发展受到了极大抑制。表明E-选择素是MRL/LPR小鼠中临界分子诱导的微血管损伤。较少的