权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
10029222
负责人：
DOMINIC J CIAVATTA
金额：
$ 67.88万
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/10029222
关键词：
Adaptive Immune System Agammaglobulinaemia tyrosine kinase Animal Model Antibodies Antineutrophil Cytoplasmic Antibodies Autoantibodies Autoantigens 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 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