AUTOIMMUNITY CENTERS OF EXCELLENCE

自身免疫卓越中心

• 批准号: 7258342
• 负责人: Leonard Chess
• 金额: $ 83.78万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-28 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7258342
• 关键词: AUTOIMMUNITY; CENTERS; EXCELLENCE

DESCRIPTION (provided by applicant): The overall goals of this ACE renewal application will be to further develop our interdisciplinary basic and clinical research program at Columbia primarily focused on the evaluation of novel therapeutic approaches to human autoimmune diseases including systemic lupus erythematosus (SLE), rheumatoid and psoriatic arthritis (RA), multiple sclerosis (MS), type I diabetes mellitus (TIDM), biliary cirrhosis and scleroderma. In each of these diseases, there are ongoing basic and clinical research programs involving pathophysiologic and/or clinical immunotherapeutic studies. We hypothesize that there are four principal events involved in the immunopathogenesis of these diseases: (1) predisposing genes establish a T-cell repertoire capable of recognizing self peptides intrinsic to the autoimmune process; (2) previously tolerant autoreactive T-cell clones are activated, expand to change the T cell repertoire to reflect autoreactive effector T cells and migrate to sites of inflammation; (3) regulatory mechanisms, including cytokines and CD4+ and CD8+ regulatory T cells fail and (4) pathogenic autoantibodies and T cells effect tissue injury. We predict that reducing the clonal expansion and migration of relevant autoreactive T cells by blockade of TCR signaling with agents like anti-CD3 or interruption of the signaling and migration of autoreactive memory T cells with agents like anti-VLA-1 could down-modulate disease activity. We propose to test these hypotheses during the natural history of disease and during specific immune intervention. In this ACE renewal, we plan to continue ongoing studies of anti-CD3 therapy of TIDM, initiate trials of biliary cirrhosis employing Mycophenolate Mofetil and continue pre-clinical assessment of the VLA-1 pathway as a prelude to clinical trials with anti-VLA-1 moAbs anticipated to begin in 2004. During these studies, we will: (1) identify by PCR based CDR3 length techniques and TCR sequencing, autoantigen-driven expansions in the CD4 and CD8 cz_ TCR repertoire; (2) Identify changes in the T cell functional response to autoantigens and (3) directly study the regulatory interactions of TH1, TH2 as well as CD4+ and CD8+ T cells in controlling the TCR repertoire. In select patients, we will directly study cells at the site of inflammation (CNS, skin, kidney, joints) using HVS immortalization techniques as well as by laser capture technology for repertoire and microarray analysis of activated genes. In addition, we plan new basic studies of the control of the autoreactive T cell repertoire in autoimmune disease by analysis of EAE in the mouse and studies of human regulatory cells in TIDM.

描述（由申请人提供）： The overall goals of this ACE renewal application will be to further develop our interdisciplinary basic and clinical research program at Columbia primarily focused on the evaluation of novel therapeutic approaches to human autoimmune diseases including systemic lupus erythematosus (SLE), rheumatoid and psoriatic arthritis (RA), multiple sclerosis (MS), type I diabetes mellitus (TIDM),胆道肝硬化和硬皮病。在每种疾病中，都有涉及病理生理和/或临床免疫治疗研究的持续基础和临床研究计划。 我们假设这些疾病的免疫病作用涉及四个主要事件：（1）诱发基因建立了能够识别自身免疫过程固有的自我肽的T细胞库； （2）以前耐受的自动反应性T细胞克隆被激活，扩展以改变T细胞库，以反映自动反应性效应T细胞并迁移到炎症部位； （3）调节机制，包括细胞因子，CD4+和CD8+调节T细胞失败，以及（4）致病性自身抗体和T细胞会影响组织损伤。 我们预测，通过阻断抗CD3（例如抗CD3）的TCR信号传导的阻断或与抗VLA-1（例如抗VLA-1）的自动反应性记忆T细胞的信号传导和迁移，通过阻断TCR信号传导来减少克隆膨胀和相关自身反应性T细胞的迁移。我们建议在疾病的自然史和特定的免疫干预期间检验这些假设。在这种王牌更新中，我们计划继续对TIDM的抗CD3疗法进行持续的研究，启动对采用霉酚酸酯莫菲替尔的胆道肝硬化的试验，并继续对VLA-1途径进行临床前评估，作为在2004年以前的per-vla-1 Moabs进行临床试验的临床试验的序列，以此为基于这些研究。 CD4和CD8 CZ_ TCR曲目中的技术和TCR测序，自动驱动的扩展； （2）确定T细胞对自身抗原的功能响应的变化，（3）直接研究TH1，TH2以及CD4+和CD8+ T细胞的调节相互作用，以控制TCR库。在某些患者中，我们将使用HVS永生技术以及通过激活基因的曲目和微阵列分析的激光捕获技术直接研究炎症部位（CNS，皮肤，肾脏，关节）的细胞。此外，我们计划通过分析小鼠中EAE的EAE和TIDM中人类调节细胞的研究来控制自身免疫性疾病中自身反应性T细胞库的新基础研究。

项目成果

Effect of interferon alpha on MHC class II gene expression in ex vivo human islet tissue.

干扰素α对离体人胰岛组织中MHC II类基因表达的影响。

• DOI: 10.1016/j.bbadis.2006.05.001
• 发表时间: 2006
• 期刊: Biochimica et biophysica acta
• 作者: Harris,PaulE;Malanga,Donatella;Liu,Zhuoro;Hardy,MarkA;Souza,Fabiola;DelPozzo,Giovanna;Winchester,RobertJ;Maffei,Antonella
• 通讯作者: Maffei,Antonella

The genetics of autoimmune-mediated rheumatic diseases: clinical and biologic implications.

自身免疫介导的风湿性疾病的遗传学：临床和生物学意义。

• DOI: 10.1016/s0889-857x(03)00112-1
• 发表时间: 2004
• 期刊: Rheumatic diseases clinics of North America.
• 作者: Winchester,Robert

The specificity of T cell regulation that enables self-nonself discrimination in the periphery.

T 细胞调节的特异性使得周围环境能够进行自我-非自我歧视。

• DOI: 10.1073/pnas.0811843106
• 发表时间: 2009
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Wu,Yilun;Zheng,Zongyu;Jiang,Yihua;Chess,Leonard;Jiang,Hong
• 通讯作者: Jiang,Hong

Immunologic characteristics of intrarenal T cells: trafficking of expanded CD8+ T cell β-chain clonotypes in progressive lupus nephritis.

• DOI: 10.1002/art.33488
• 发表时间: 2012-05
• 期刊: ARTHRITIS AND RHEUMATISM
• 作者: Winchester, Robert;Wiesendanger, Margrit;Zhang, Hui-Zhu;Steshenko, Valeria;Peterson, Karin;Geraldino-Pardilla, Laura;Ruiz-Vazquez, Elena;D'Agati, Vivette
• 通讯作者: D'Agati, Vivette