Investigation and Development of New Therapeutic Avenues for Scleroderma

硬皮病新治疗途径的研究和开发

• 批准号: 8792820
• 负责人: Emanual M. Maverakis
• 金额: $ 51.03万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8792820
• 关键词: Affinity; Autoimmune Diseases; Autoimmunity; Belief; Binding; Cells; Common Cold; Development; Disease; Immune; Immune response; Immune system; Immunosuppressive Agents; Infection; Investigation; Libraries; Ligands; Mediating; Organ; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Population; Publishing; Refractory; Role; Scleroderma; Systemic Scleroderma; T-Cell Activation; T-Lymphocyte; Techniques; Technology; Therapeutic; Therapeutic immunosuppression; Tissues; abstracting; base; combinatorial; design; effective therapy; fighting; improved; inhibitor/antagonist; new therapeutic target; novel; novel therapeutics; public health relevance; screening; skin disorder; small molecule

DESCRIPTION (Provided by the applicant) Abstract: Currently there is no effective treatment for Scleroderma (systemic sclerosis), an autoimmune disease unresponsive to immunosuppressive therapy. This proposal is based upon the belief that two main barriers exist towards the cure of this disease. First, there is no published technology for isolating unmanipulated pathogenic T cells from patients with autoimmunity. Second, current immunosuppressive medications do not target the correct immune cells in these patients. In order to improve the treatment and survival of these patients it is critical to: identify the role that the immune system plays in this disease, determine the effect that current immunosuppressive therapies have on the patients' autoreactive immune response, identify new therapeutic targets by fully characterizing the autoreactive immune response in scleroderma, and finally to design novel inhibitors to these targets. Our specific hypothesis is that unmanipulated self- reactive T cell clones isolated directly from patients with scleroderma can be used to identify novel therapeutic targets and small molecules capable of selectively binding these pathogenic cells. This hypothesis is based upon the following observations. 1) We have developed a technique to directly isolate pure populations of clonally expanded T cells from patients with autoimmunity. 2) A high affinity ligand for a subpopulation of activated T cells was identified through a combinatorial screening approach. 3) Screening combinatorial libraries has identified inhibitors of key intracellular pathway required for T cell activation. Based upon these observations the experimental focus of this proposal will be to combinatorial libraries to identify novel T cell-inhibiting small molecules and T cell-specific ligands in an attempt to develop a highly effective therapeutic that can target and destroy pathogenic T cells in the setting of scleroderma and other immune mediated diseases of the skin.

描述（由申请人提供） 摘要：目前还没有有效的治疗硬皮病（系统性硬化症），一种自身免疫性疾病免疫抑制治疗无反应。这项建议是基于这样一种信念，即在治愈这种疾病方面存在两个主要障碍。首先，没有公开的技术用于从自身免疫患者中分离未经操作的致病性T细胞。其次，目前的免疫抑制药物并没有针对这些患者的正确免疫细胞。为了改善这些患者的治疗和生存，关键是：确定免疫系统在这种疾病中发挥的作用，确定目前的免疫抑制疗法对患者自身反应性免疫应答的影响，通过充分表征硬皮病中的自身反应性免疫应答来确定新的治疗靶点，并最终设计针对这些靶点的新型抑制剂。我们的具体假设是，直接从硬皮病患者分离的未经操作的自身反应性T细胞克隆可用于鉴定新的治疗靶点和能够选择性结合这些致病细胞的小分子。这一假设基于以下观察。1)我们已经开发了一种技术，直接从自身免疫患者中分离克隆扩增的纯T细胞群。2)通过组合筛选方法鉴定了活化T细胞亚群的高亲和力配体。3)筛选组合文库已经鉴定了T细胞活化所需的关键细胞内途径的抑制剂。基于这些观察结果，本提案的实验重点将是组合文库以鉴定新的T细胞抑制性小分子和T细胞特异性配体，以尝试开发一种高效的治疗剂，其可以在硬皮病和其他免疫介导的皮肤疾病的背景下靶向并破坏致病性T细胞。

项目成果

Classic Ulcerative Pyoderma Gangrenosum Is a T Cell-Mediated Disease Targeting Follicular Adnexal Structures: A Hypothesis Based on Molecular and Clinicopathologic Studies.

经典的溃疡性脓疱性坏疽是一种T细胞介导的靶向卵泡附件结构的疾病：基于分子和临床病理学研究的假设。

• DOI: 10.3389/fimmu.2017.01980
• 发表时间: 2017
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Wang EA;Steel A;Luxardi G;Mitra A;Patel F;Cheng MY;Wilken R;Kao J;de Ga K;Sultani H;Merleev AA;Marusina AI;Brassard A;Fung MA;Konia T;Shimoda M;Maverakis E
• 通讯作者: Maverakis E

Glycan biomarkers of autoimmunity and bile acid-associated alterations of the human glycome: Primary biliary cirrhosis and primary sclerosing cholangitis-specific glycans.

自身免疫和胆汁酸相关的人类糖组改变的聚糖生物标志物：原发性胆汁性肝硬化和原发性硬化性胆管炎特异性聚糖。

• DOI: 10.1016/j.clim.2021.108825
• 发表时间: 2021
• 期刊: Clinical immunology (Orlando, Fla.)
• 作者: Maverakis,Emanual;Merleev,AlexanderA;Park,Dayoung;Kailemia,MuchenaJ;Xu,Gege;Ruhaak,LRenee;Kim,Kyoungmi;Hong,Qiuting;Li,Qiongyu;Leung,Patrick;Liakos,William;Wan,Yu-JuiYvonne;Bowlus,ChristopherL;Marusina,AlinaI;Lal,Nelvish
• 通讯作者: Lal,Nelvish

International consensus criteria for the diagnosis of Raynaud's phenomenon.

• DOI: 10.1016/j.jaut.2014.01.020
• 发表时间: 2014-02
• 期刊: Journal of autoimmunity
• 影响因子: 12.8
• 作者: Maverakis E;Patel F;Kronenberg DG;Chung L;Fiorentino D;Allanore Y;Guiducci S;Hesselstrand R;Hummers LK;Duong C;Kahaleh B;Macgregor A;Matucci-Cerinic M;Wollheim FA;Mayes MD;Gershwin ME
• 通讯作者: Gershwin ME