Development of disease-specific diagnosis and immunotherapy for Sjogren's syndrome

干燥综合征的疾病特异性诊断和免疫治疗的发展

基本信息

  • 批准号:
    12557022
  • 负责人:
  • 金额:
    $ 8.51万
  • 依托单位:
  • 依托单位国家:
    日本
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
  • 财政年份:
    2000
  • 资助国家:
    日本
  • 起止时间:
    2000 至 2001
  • 项目状态:
    已结题

项目摘要

Previously we have identified a 120 kD α-fodrin as a common autoantigen in the pathogenesis of primary Sjogren's syndrome (SS) in humans, but the mechanisms underlying the immunodominant epitope recognition remain unclear. SS in human is a T cell-mediated autoimmune disease in the salivary and lacrimal glands, leading to clinical symptoms of dryness of the mouth and eyes (sicca syndrome). Recombinant α-fodrin protein, the cDNA encoding human α-fodrin (JS-1) was constructed by inserting cDNA into EcoR1 site of pGEX-2T, To establish disease-specific diagnostic system, approximately 200 sera from patients with SS were tested with ELISA assay using JS-1 recombinant protein. Autoreactive T cell clones that recognize synthetic N-terminal portion of α-fodrin autopeptide were established, which produced Th1 cytokines, and showed cytotoxic activities. Alanine scanning mutagenesis of the epitope peptide indicate that the two amino acid substitutions of MHC contact points within epitope are sufficient to alter peptide binding and MHC restriction. Moreover, it is evident that only two TCR contact points are essential for initiation of antigen-specific T cell response. An analogue peptide-based vaccination prevented the disease through downregulation of Th1 responses and autoantibody production. Blockade of pathogenic T cell activity through an analogue peptide-based immunotherapy is highly effective for T cell-mediated autoimmune disease such as human SS.
此前,我们已经鉴定出 120 kD α-fodrin 是人类原发性干燥综合征 (SS) 发病机制中常见的自身抗原,但免疫显性表位识别的机制仍不清楚。人类SS是一种T细胞介导的唾液腺和泪腺自身免疫性疾病,导致口腔和眼睛干燥(干燥综合征)的临床症状。通过将 cDNA 插入 pGEX-2T 的 EcoR1 位点,构建了重组 α-fodrin 蛋白,即编码人 α-fodrin (JS-1) 的 cDNA。为了建立疾病特异性诊断系统,使用 JS-1 重组蛋白对约 200 份 SS 患者血清进行了 ELISA 检测。建立了识别 α-fodrin 自肽合成 N 末端部分的自身反应性 T 细胞克隆,其产生 Th1 细胞因子,并表现出细胞毒活性。表位肽的丙氨酸扫描诱变表明表位内 MHC 接触点的两个氨基酸取代足以改变肽结合和 MHC 限制。此外,很明显,只有两个 TCR 接触点对于启动抗原特异性 T 细胞反应至关重要。基于类似肽的疫苗接种通过下调 Th1 反应和自身抗体的产生来预防这种疾病。通过基于类似肽的免疫疗法阻断致病性 T 细胞活性对于 T 细胞介导的自身免疫性疾病(例如人类 SS)非常有效。

项目成果

期刊论文数量(48)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Azuma,M. et al.: "Cepharantine suppresses tumor necrosis factor-α-induced matrix metalloproteinase-9- production by downregulating nuclear factor kB in human salivary gland acinar cells"Arthritis Rheum. (in press). (2002)
Azuma, M. 等人:“Cepharantine 通过下调人唾液腺腺泡细胞中的核因子 kB 来抑制肿瘤坏死因子 α 诱导的基质金属蛋白酶 9 的产生”Arthritis Rheum(出版中)。
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    0
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Yoshio Hayashi et al.: "Involvement of apoptotic protease cascade for tissue destruction in Sjogren's syndrome"Arch.Immunol.Ther.Exp.. 48. 399-403 (2000)
Yoshio Hayashi 等:“凋亡蛋白酶级联对干燥综合征中组织破坏的参与”Arch.Immunol.Ther.Exp.. 48. 399-403 (2000)
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    0
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Maeno, N. et al.: "Anti-α-fodrin antibodies in Sjogren's syndrome in chirldren"J. Rheumatol.. 28. 860-864 (2001)
Maeno, N. 等人:“儿童干燥综合征中的抗 α-fodrin 抗体”J. Rheumatol.. 28. 860-864 (2001)
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    0
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Kobayashi, I. et al.: "Antii-α-fodrin autoantibody is an early diagnostic maker for childhood primary Siogren's syndrome"J. Rheumatol. 28. 363-365 (2001)
Kobayashi, I. 等人:“抗 α-fodrin 自身抗体是儿童原发性 Siogren 综合征的早期诊断指标”J.Rheumatol. 28. 363-365 (2001)
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  • 影响因子:
    0
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Kaoru Saegusa et al: "Mechanisms of neonatal tolerance induced in an animal model for primary Sjogren's syndrome by intravenous administration of autoantigen. "Scand.J.Immunol.. 52. 264-270 (2000)
Kaoru Saegusa 等人:“通过静脉注射自身抗原在原发性干燥综合征动物模型中诱导新生儿耐受的机制。”Scand.J.Immunol.. 52. 264-270 (2000)
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HAYASHI Yoshio其他文献

HAYASHI Yoshio的其他文献

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{{ truncateString('HAYASHI Yoshio', 18)}}的其他基金

Study on Medicinal Chemistry of Reversible Cysteine Protease Inhibitors for the Treatment of Infectious Diseases
可逆性半胱氨酸蛋白酶抑制剂治疗感染性疾病的药物化学研究
  • 批准号:
    23659059
  • 财政年份:
    2011
  • 资助金额:
    $ 8.51万
  • 项目类别:
    Grant-in-Aid for Challenging Exploratory Research
Integrated medicinal chemistry research of intractable diseases based on peptidic small molecules
基于肽类小分子的疑难杂症综合药物化学研究
  • 批准号:
    23390029
  • 财政年份:
    2011
  • 资助金额:
    $ 8.51万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Immunotherapeutic analysis using newly established murine models for Sjogren' s syndrome
使用新建立的干燥综合征小鼠模型进行免疫治疗分析
  • 批准号:
    21249090
  • 财政年份:
    2009
  • 资助金额:
    $ 8.51万
  • 项目类别:
    Grant-in-Aid for Scientific Research (A)
Study on Medicinal Chemistry, Chemical Biology and Chemical Pharmaceutics of Anticancer Drug Based on the Microtubule Targeting Agents
基于微管靶向药物的抗癌药物化学、化学生物学和化学药剂学研究
  • 批准号:
    20390036
  • 财政年份:
    2008
  • 资助金额:
    $ 8.51万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Molecular analysis of pathogenesis on Sjogren's syndrome and its application of new diagnosis and therapy
干燥综合征发病机制的分子分析及其在新诊治中的应用
  • 批准号:
    17109016
  • 财政年份:
    2005
  • 资助金额:
    $ 8.51万
  • 项目类别:
    Grant-in-Aid for Scientific Research (S)
Development of Anticancer and Antiviral Agents Based on Diketopiperazine as a Bio-function-Mimicking Molecular Platform
基于二酮哌嗪作为生物功能模拟分子平台的抗癌和抗病毒药物的开发
  • 批准号:
    15590102
  • 财政年份:
    2003
  • 资助金额:
    $ 8.51万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Development research into history chronology system that can share collaborative activity and data by network
可通过网络共享协作活动和数据的历史年代学系统的开发研究
  • 批准号:
    15500152
  • 财政年份:
    2003
  • 资助金额:
    $ 8.51万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Chemical composition and point source of high energy primary cosmic ray and sidereal time variation
高能初级宇宙线的化学成分、点源和恒星时变
  • 批准号:
    15403005
  • 财政年份:
    2003
  • 资助金额:
    $ 8.51万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Molecular Function of Naturally Occurring Anti-microtubule Agent Phenylahistin (Determination of Structural Components Necessary for the Anti-microtubule activity t and Molecular Design for Drugs)
天然存在的抗微管剂苯拉西汀的分子功能(抗微管活性所需结构成分的测定和药物分子设计)
  • 批准号:
    12672162
  • 财政年份:
    2000
  • 资助金额:
    $ 8.51万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Analysis of the mechanism of membranous proteolysis and the immunoregulation for Sjogren's syndrome
干燥综合征膜蛋白水解机制及免疫调节分析
  • 批准号:
    12307040
  • 财政年份:
    2000
  • 资助金额:
    $ 8.51万
  • 项目类别:
    Grant-in-Aid for Scientific Research (A)

相似海外基金

Exploring Roles for Transcription Factor Ets1 in Sjogren's Syndrome
探索转录因子 Ets1 在干燥综合征中的作用
  • 批准号:
    10644080
  • 财政年份:
    2023
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    $ 8.51万
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Aging and Oxidative Stress Influence Salivary Gland Disease in Sjogren's Syndrome
衰老和氧化应激对干燥综合征唾液腺疾病的影响
  • 批准号:
    10682148
  • 财政年份:
    2023
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    $ 8.51万
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Sjogren's Syndrome Pathogenic Autoantibodies
干燥综合征致病性自身抗体
  • 批准号:
    10854472
  • 财政年份:
    2023
  • 资助金额:
    $ 8.51万
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Controlling Autoimmune Inflammation and Promoting Salivary Gland Regeneration in Sjogren's Syndrome
控制干燥综合征的自身免疫炎症并促进唾液腺再生
  • 批准号:
    10528045
  • 财政年份:
    2022
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    $ 8.51万
  • 项目类别:
Harnessing molecular signatures to deliver personalised B-cell targeted therapies in Sjogren's syndrome
利用分子特征为干燥综合征提供个性化 B 细胞靶向治疗
  • 批准号:
    MR/X004694/1
  • 财政年份:
    2022
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    $ 8.51万
  • 项目类别:
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Targeting Endogenous Mesenchymal Stromal Cells with Ruxolitinib to Treat Sialadenitis in Sjogren's Syndrome
用鲁索替尼靶向内源性间充质基质细胞治疗干燥综合征的唾液腺炎
  • 批准号:
    10646349
  • 财政年份:
    2022
  • 资助金额:
    $ 8.51万
  • 项目类别:
Targeting Endogenous Mesenchymal Stromal Cells with Ruxolitinib to Treat Sialadenitis in Sjogren's Syndrome
用鲁索替尼靶向内源性间充质基质细胞治疗干燥综合征的唾液腺炎
  • 批准号:
    10524424
  • 财政年份:
    2022
  • 资助金额:
    $ 8.51万
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Targeting P2 Receptors to Restore Salivary and Lacrimal Gland Function in Sjogren's Syndrome
靶向 P2 受体以恢复干燥综合征患者的唾液腺和泪腺功能
  • 批准号:
    10685136
  • 财政年份:
    2022
  • 资助金额:
    $ 8.51万
  • 项目类别:
Controlling Autoimmune Inflammation and Promoting Salivary Gland Regeneration in Sjogren's Syndrome
控制干燥综合征的自身免疫炎症并促进唾液腺再生
  • 批准号:
    10657745
  • 财政年份:
    2022
  • 资助金额:
    $ 8.51万
  • 项目类别:
Targeting P2 Receptors to Restore Salivary and Lacrimal Gland Function in Sjogren's Syndrome
靶向 P2 受体以恢复干燥综合征患者的唾液腺和泪腺功能
  • 批准号:
    10554383
  • 财政年份:
    2021
  • 资助金额:
    $ 8.51万
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