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Pathobiology of ANCA Glomerulonephritis: Targeting Adaptive and Innate Immune Processes for Precision Therapies

ANCA 肾小球肾炎的病理学：针对适应性和先天免疫过程进行精准治疗

基本信息

批准号：
10190933
负责人：
DOMINIC J CIAVATTA
金额：
$ 67.78万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
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：
2020-07-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10190933
关键词：
Adaptive Immune System Agammaglobulinaemia tyrosine kinase Animal Model Antibodies Antineutrophil Cytoplasmic Antibodies Autoantibodies Autoantigens Autoimmune Autoimmune Diseases Autoimmune Process Autoimmune Responses Autoimmunity B-Lymphocyte Subsets B-Lymphocytes Biology Cell Adhesion Molecules Cell Therapy Cells Clinical Clinical Trials Complement Complex DNA Methylation Data Development Disabled Persons Disease Disease remission Elements Engineering Epigenetic Process Epitope Mapping Epitopes FOXP3 gene Foundations Future Gene Expression Genetic Recombination Genetic Transcription Glomerulonephritis Goals Granulomatous Harvest Immune Immune Targeting Immune system Immunocompetent Immunosuppressive Agents Immunotherapy In Vitro Infection Injury Innate Immune Response Innate Immune System Knowledge Lead Life Lymphocyte Function-Associated Antigen-1 Macrophage-1 Antigen Mediating Mediator of activation protein Modeling Molecular Mus PRTN3 gene Pathogenesis Pathogenicity Patients Peroxidases Play Population Population Heterogeneity Pre-Clinical Model Precision therapeutics Process Protein Biosynthesis Protein Tyrosine Kinase Proteinase 3 Proteins RNA Splicing Regulatory T-Lymphocyte Risk Role Signal Pathway T-Cell Receptor T-Lymphocyte Techniques Technology Testing Toxic effect Transcriptional Regulation Transplantation United States Food and Drug Administration Variant Vasculitis Wild Type Mouse Work Yeasts autoreactive B cell beta-Chemokines cellular engineering cellular targeting chemokine receptor chimeric antigen receptor T cells design experimental study granulocyte histone methylation immunomodulatory therapies immunoregulation individual patient innate immune mechanisms monocyte mouse model neutrophil novel novel strategies novel therapeutic intervention novel therapeutics personalized medicine pre-clinical receptor response scalpel side effect targeted treatment therapy development tissue injury

项目摘要

ABSTRACT Anti-neutrophil cytoplasmic autoantibodies (ANCA) glomerulonephritis (GN) is a life-threatening autoimmune disease. While current immunosuppressive agents produce remission in the majority of patients, our treatment has had precision more akin to a chainsaw rather than a scalpel. The lack of specific, targeted immune therapy leaves patients with an overly handicapped immune system and a host of toxic side effects. Our proposal seeks to to finally advance the field toward more precise and targeted therapies with far less potential for harm. Building upon our prior body of work, we will attempt to exploit the adaptive autoimmune responses seen in ANCA GN as targets for immunomodulatory therapies by multiple approaches. By using our previously developed epitope mapping techniques, we will engineer chimeric autoantibody receptor (CAAR) T cells that will specifically target only those B cells that express the pathogenic ANCA antibody epitopes. In another approach, we will profile the heterogeneous population of T regulatory cells. After identifying those that are fully suppressive, we will attempt to expand this population in vitro and confirm that they retain their suppressive function. This work will determine whether in future studies, we can first harvest these cells from ANCA GN patients, expand them in vitro, and reintroduce them into patients to provide immunomodulatory effects that would reintroduce autoimmune tolerance. Utilizing our well-characterized mouse model of myeloperoxidase (MPO) ANCA GN, we will explore the mechanisms by which T (and B) regulatory cells suppress autoimmunity and leverage this knowledge to develop pre-clinical models of T regulatory cell therapy. In addition to the potential role of cell-based therapies, we will explore the role of the innate immune system in ANCA GN using our established MPO mouse model and novel models that we have developed of granulomatous disease. These models will also us to identify components of the innate immune response that may be amenable to novel therapies. Further, we will determine whether we can manipulate the epigenetic changes that alter expression of the autoantigen proteins targeted by the autoimmune processes that drive ANCA GN. These foundational studies have been designed with the intent to inform Investigative New Drug (IND) applications to the Food and Drug Administration (FDA). This work will usher in a new therapeutic era for ANCA GN, characterized by greater precision, less toxicity and perhaps, longer duration.

摘要抗中性粒细胞胞浆抗体（ANCA）肾小球肾炎（GN）是一种危及生命的疾病，自身免疫性疾病虽然目前的免疫抑制剂在大多数患者中产生缓解，我们的治疗更像是电锯而不是手术刀。缺乏针对性、针对性免疫疗法使患者的免疫系统过度受损，并产生大量毒副作用。我们该提案旨在最终推动该领域朝着更精确和更有针对性的治疗方向发展，而潜力要小得多伤害。在我们先前工作的基础上，我们将尝试利用所见的适应性自身免疫反应，在ANCA GN中，通过多种方法作为免疫调节治疗的靶点。通过使用我们以前的开发表位作图技术，我们将工程嵌合自身抗体受体（CAAR）T细胞，仅特异性靶向表达致病性ANCA抗体表位的那些B细胞。在另一种方法中，我们将分析调节性T细胞的异质群体。在确定了那些完全抑制性，我们将尝试在体外扩大这一群体，并确认他们保留其抑制性，功能这项工作将决定在未来的研究中，我们是否可以首先从ANCA GN中收获这些细胞患者，在体外扩增它们，并将它们重新引入患者体内以提供免疫调节作用，会重新引入自身免疫耐受利用我们良好表征的髓过氧化物酶小鼠模型 (MPO)ANCA GN，我们将探索T（和B）调节细胞抑制自身免疫的机制并利用这些知识来开发调节性T细胞治疗的临床前模型。除了基于细胞的治疗的潜在作用外，我们还将探索先天免疫的作用。使用我们建立的MPO小鼠模型和我们开发的新模型，肉芽肿病这些模型也将帮助我们识别先天免疫反应的组成部分，可能适用于新的治疗方法。此外，我们将确定我们是否可以操纵表观遗传改变自身免疫过程靶向的自身抗原蛋白表达的变化， ANCA GN. 这些基础研究旨在为研究性新药（IND）提供信息向食品和药物管理局（FDA）提出申请。这项工作将为ANCA开创一个新的治疗时代 GN的特点是更精确，毒性更小，可能持续时间更长。