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Pathogenicity of memory Th17 cells in chronic autoimmune uveitis

记忆性Th17细胞在慢性自身免疫性葡萄膜炎中的致病性

基本信息

批准号：
10216752
负责人：
YIHE CHEN
金额：
$ 29.55万
依托单位：
SCHEPENS EYE RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10216752
关键词：
Acute Acute Disease Address Adoptive Transfer Adrenal Cortex Hormones Affect Animal Experimentation Animal Model Animals Antigens Antimetabolites Autoimmune Diseases Biological Products Blindness CCL20 gene CCR6 gene CD4 Positive T Lymphocytes CD44 gene Cells Chronic Chronic Disease Clinical Clinical Course of Disease Clinical Management Clinical Trials Cyclosporine Cytotoxic agent Development Diabetic Retinopathy Disease Disease Resistance Economic Burden Electroretinography Experimental Autoimmune Encephalomyelitis Eye diseases Failure Foundations Frequencies Future Health Care Costs High Prevalence Human IL2RA gene Immune Immune response Immunologic Memory In Vitro Infiltration Inflammation Inflammatory Inflammatory Bowel Diseases Interleukin-17 Laboratories Legal Blindness Lymphoid Tissue Maintenance Mediating Medical Memory Modeling Molecular Mouse Strains Mus Pathogenesis Pathogenicity Patients Phenotype Play Population Process Production Progressive Disease Rag1 Mouse Research Resistance Resistance Process Resolution Rest Retina Role SELL gene Series Severity of illness Solid Supplementation T memory cell T-Lymphocyte Therapeutic Tissues Uveitis Virulence Factors Visual impairment Work aging population autoimmune uveitis cytokine efficacious treatment experience immunomodulatory strategy improved in vivo interleukin-15 receptor migration mouse model novel novel therapeutic intervention ocular surface productivity loss response side effect socioeconomics targeted treatment translational study

项目摘要

PROJECT SUMMARY / ABSTRACT Chronic autoimmune uveitis is often a treatment-resistant disease, leading to irreversible vision loss in a significant number of patients thus affected. With particularly high prevalence in the working-age population, it accounts for 10-15% of legal blindness in the US, and adds a substantial socio-economic burden due to consequent healthcare costs and productivity loss, estimated to be close to that of diabetic retinopathy. The preponderance of previous studies investigating autoimmune uveitis have focused on the acute stage of the disease using the popular murine models of acute uveitis, which in fact uncommonly leads to severe vision loss in humans in contrast to chronic uveitis. Thus, there is a major deficiency in our current understanding of the precise pathogenic mechanisms in chronic autoimmune uveitis. This deficiency has been associated with the recently unexpected failure of several clinical trials, which had promising translational potential as a therapeutic strategy from animals with acute uveitis to human patients with chronic uveitis. Our laboratory has now developed and validated a mouse model of chronic autoimmune uveitis (CAU) in wild-type animals, which presents with a slow-onset, progressive disease course for an observed duration of 3 months, replicating the clinical features of chronic progressive uveitis observed in humans. We hope to use this animal model to develop a deeper understanding of the immunopathogenesis of uveitis during the chronic stage, and thus provide a solid foundation for prioritizing the development of new targeted treatment in human patients. Our preliminary work in the CAU model has detected a prominent memory T helper-17 cells (mTh17), and this unique cell population from CAU has demonstrated vigorous responses to uveitogenic antigen stimulation in vitro. Memory T cells are antigen-experienced, long-lived T lymphocytes mediating immunological memory. Increasing evidence has demonstrated that immunological memory plays a critical role in autoimmune disorders and chronic inflammation. We thus hypothesize that memory Th17 cells are specific uveitogenic effectors and mediate the chronic disease course of uveitis. The principal objectives of this project are to (i) precisely characterize the phenotype and function of mTh17 in CAU; and (ii) determine the function of mTh17 in the maintenance of chronicity of uveitis. To achieve these objectives, two specific aims have been developed: Aim 1: Are mTh17 featured as `effector memory' T cells capable of inducing uveitis? And Aim 2: Will supplementation or depletion of mTh17 affect the disease course in established acute or chronic uveitis, respectively? Successful completion of this project will provide a framework for the development of novel therapeutic approaches precisely targeting the underlying cause of disease chronicity – a process resistant to the currently available treatment and leading to severe visual impairment.

项目摘要/摘要