Analysis of regulatory mechanisms for HMGB1 secretion and signal transduction and their clinical significance

HMGB1分泌及信号转导调控机制分析及其临床意义

• 批准号: 16390517
• 负责人: OZAKI Shoichi
• 金额: $ 9.09万
• 依托单位: St.Marianna University School of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390517/
• 关键词: HMGB1; HMGB1 receptors; Signal transduction; B-cell epitopes; cytotoxic T cells; T-cell epitopes; Hepatic-failure models; HMGB1-absorption therapy; マクロファージ; エピトープ; 好中球

We isolated high mobility group (HMG) nonhisitone chromosomal proteins 1 and 2 (HMGB1/HMGB2) as target antigens of anti-neutrophil cytoplasmic antibody, and have been analyzing the roles of those autoantibodies as well as the autoantigens.In this study, we found that the major B-cell epitope of a monoclonal anti-HMGB1 antibody, FBH7, is a combinatorial structure which is constructed by amino acid residue 52-56, ant that this portion is different between neutrophil-derived and lymphocyte-derived HMGB1 (J.Biochem.136;155,2004). We also analyzed the HMGB1 epitopes that were recognized by serum antibodies derived from patients with various autoimmune diseases : rheumatic diseases, inflammatory bowel diseases, and autoimmune liver diseases. Although we have not completed the epitope mapping, data obtained so far indicate that some sera recognize the similar epitope.The T-cell epitope of HMGB1 was investigated by measuring the affinity to bind to HLA-A2.1. We revealed that the 9-mer of HMGB1 12-20 showed the similar affinity as a well-known CTL epitope, p17-WT. These results suggest that HMGB1 may induce CTL restricted to HLA-A2.1.We also established a novel fatal mouse model, in which 90% of the hepatic blood flow was blocked by a surgical procedure. All mice died 60 hr after the ligation with a median survival time of 30 hr. These mice showed an elevated level of serum HMG1, and the survival rate increased by a simultaneous i.p.injection of monoclonal anti-HMG1 antibody (J.Surg.Res.124:59,2005). Taken together, these data indicates that HMG1 protein may play an important role in a certain fatal condition, and that the intervention of serum HMG1 levels may serve as a new strategy for such a critical state. For that purpose, we started to establish a biological membrane that can absorb HMGB1 effectively.

我们分离了高迁移率族(HMG)非组酮染色体蛋白1和2(HMGB1/HMGB2)作为抗中性粒细胞胞浆抗体的靶抗原，并分析了这些自身抗体和自身抗原的作用。在本研究中，我们发现抗HMGB1单抗FBH7的主要B细胞表位是由氨基酸残基52-56组成的组合结构，这一部分在中性粒细胞来源的HMGB1和淋巴细胞来源的HMGB1中是不同的(J.BioChem.136；155,2004)。我们还分析了各种自身免疫性疾病患者的血清抗体识别的HMGB1表位：风湿性疾病、炎症性肠病和自身免疫性肝病。虽然我们还没有完成表位映射，但到目前为止获得的数据表明，一些血清识别相似的表位。通过测量HMGB1与人类白细胞抗原A2.1的亲和力来研究HMGB1的T细胞表位。我们发现，HMGB112-20的9-聚体与广为人知的CTL表位p17-WT具有相似的亲和力。这些结果表明，HMGB1可以诱导针对人类白细胞抗原A2.1的CTL。我们还建立了一种新的致死小鼠模型，通过外科手术阻断了90%的肝脏血流量。所有小鼠在结扎后60小时全部死亡，中位存活时间为30小时。这些小鼠的血清HMG1水平升高，同时腹腔注射抗HMG1单抗可提高存活率(J.Surg.Resg.124：59,2005)。综上所述，这些数据表明HMG1蛋白可能在特定的致死状态中发挥重要作用，干预血清HMG1水平可能是治疗这种危重状态的一种新策略。为此，我们开始建立一种能够有效吸附HMGB1的生物膜。

项目成果

Ameliorative effects of follistatin-related protein/TSC-36 on joint inflammation in a mouse model of arthrites.

卵泡抑素相关蛋白/TSC-36 对关节炎小鼠模型关节炎症的改善作用。

• 发表时间: 2004
• 期刊: Arthritis Rheum. 50(2)
• 作者: Kawabata D.;et al.
• 通讯作者: et al.

血管炎の新分類とその診断。リウマチ・膠原病 最新トピックス 変わりゆく研究と診療,

血管炎的新分类及其诊断。

• 发表时间: 2005
• 作者: 尾崎承一;他
• 通讯作者: 他

Association of killer cell immunoglobulin-like receptor genotypes with microscopic polyangiitis.

• DOI: 10.1002/art.21653
• 发表时间: 2006-03
• 期刊: Arthritis and rheumatism
• 作者: R. Miyashita;N. Tsuchiya;T. Yabe;Shigeto Kobayashi;H. Hashimoto;S. Ozaki;K. Tokunaga

高齢男性が持続する発熱、体重減少、多関節炎、網状皮斑、下垂足を訴えた!?シミュレイション内科 リウマチ・アレルギー疾患を探る。

一位老人主诉持续发烧、体重减轻、多关节炎、网状皮损、足下垂！？模拟内科探索风湿病和过敏性疾病。

• 发表时间: 2005
• 作者: Kumagai S.;Kumada F.;Kita T.;Morinobu A.;Ozaki S.;Ishida H.;Sano H.;Matsubara T;Okumura K.;Kawabata D. et al.;Kumagai S. et al.;Ito I.et al.;Karasawa R. et al.;尾崎承一 他;尾崎承一 他
• 通讯作者: 尾崎承一 他

血管炎症候群。Guidekine膠原病・リウマチ-治療ガイドラインをどう読む-

血管炎综合征。

• 发表时间: 2005
• 作者: 尾崎承一;他;山田秀裕
• 通讯作者: 山田秀裕