The role of IL-2 therapy for Relapsing-Remitting Chikungunya Arthritis

IL-2 治疗复发缓解型基孔肯雅关节炎的作用

基本信息

批准号：
10171790
负责人：
Aileen Chang
金额：
$ 15.52万
依托单位：
GEORGE WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10171790
关键词：
Affect Alphavirus Americas Animals Antigen-Presenting Cells Arthralgia Arthritis Autoimmune Autoimmune Diseases CD3 Antigens Cell Maturation Chikungunya virus Chronic Colombian Culicidae Data Development Disease Disease Outbreaks Disease remission Dose Enrollment Equilibrium Eragrostis Evidence based treatment FOXP3 gene Flare Florida Flow Cytometry Functional disorder Gene Mutation Goals IL2RA gene Immune response Immunology Immunosuppression Infection Infiltration Inflammatory Injections Interleukin 2 Receptor Interleukin-2 Measurement Mediating Mus Outcome Measure Pathogenesis Pathway interactions Patients Peripheral Blood Mononuclear Cell Play Population Questionnaires Reaction Regulatory T-Lymphocyte Relapse Research Rheumatoid Arthritis Rheumatology Role Serum Severities Symptoms Synovial Membrane T-Lymphocyte Subsets Therapeutic Tissues Viral Arthritis base chikungunya chikungunya infection cohort cytokine effector T cell evidence base immune activation improved insight joint inflammation mouse model novel novel therapeutics peripheral blood preclinical evaluation side effect standard care therapeutic target

项目摘要

ABSTRACT Chikungunya virus (CHIKV) is an alphavirus spread by mosquitos that causes persistent arthritis in approximately one-fourth of patients. There is currently no evidence-based standard treatment for CHIKV chronic arthritis. In the current proposal, we seek to identify a therapeutic target for relapsing-remitting arthritis associated with CHIKV infection. Our Colombian cohort (n = 500) of patients affected by CHIKV affords a unique opportunity to further understand the immunology of CHIKV arthritis flares. Our preliminary data suggest that alteration of regulatory T cell (Treg) function may play a role in CHIKV arthritis pathogenesis. Novel low-dose interleukin-2 (IL-2) based therapies for autoimmune disease have been shown to up-regulate Tregs and may be of use in CHIKV arthritis flares. Our main goal is to further understand the role of IL-2 in Treg populations in CHIKV arthritis. Our central hypothesis is that chronic CHIKV arthritis activity is associated with deficient IL-2 mediated Treg levels and low-dose IL-2 is a potential therapeutic. This hypothesis will be evaluated in two specific aims. In Aim 1, we will describe the role of IL-2 in Treg expansion and corresponding arthritis severity during CHIKV arthritis flare vs. remission compared to non-arthritic controls. In Aim 2, we will determine the role of IL-2 therapy in the treatment of CHIKV arthritis in a mouse model. The impact of this research will determine the correlation between Tregs and CHIKV-associated arthralgia. It may provide a pre-clinical evaluation of low-dose IL-2 therapy for CHIKV arthritis and insights into the use of this novel therapeutic for viral arthritis in general.

抽象的基孔肯雅病毒（CHIKV）是一种由蚊子传播的甲病毒，可引起持续性关节炎大约四分之一的患者。目前尚无针对 CHIKV 的循证标准治疗方法慢性关节炎。在当前的提案中，我们寻求确定复发缓解型关节炎的治疗靶点与 CHIKV 感染有关。我们的哥伦比亚队列 (n = 500) 受 CHIKV 影响的患者提供了进一步了解 CHIKV 关节炎发作免疫学的独特机会。我们的初步数据表明调节性 T 细胞 (Treg) 功能的改变可能在 CHIKV 关节炎发病机制中发挥作用。基于低剂量白细胞介素 2 (IL-2) 的新型自身免疫性疾病疗法已被证明可以上调 Tregs 可能用于治疗 CHIKV 关节炎发作。我们的主要目标是进一步了解 IL-2 在 CHIKV 关节炎中的 Treg 群体。我们的中心假设是慢性 CHIKV 关节炎活动是与 IL-2 介导的 Treg 水平缺陷相关，低剂量 IL-2 是一种潜在的治疗方法。这假设将在两个具体目标中进行评估。在目标 1 中，我们将描述 IL-2 在 Treg 扩增中的作用与非关节炎相比，CHIKV 关节炎发作期间相应的关节炎严重程度与缓解情况控制。在目标 2 中，我们将确定 IL-2 疗法在治疗小鼠 CHIKV 关节炎中的作用模型。这项研究的影响将确定 Tregs 和 CHIKV 相关性之间的相关性关节痛。它可以为 CHIKV 关节炎的低剂量 IL-2 疗法提供临床前评估，并深入了解这种新型疗法用于治疗病毒性关节炎。