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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：
10618839
负责人：
DOMINIC J CIAVATTA
金额：
$ 68.27万
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/10618839
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 Certification Clinical Clinical Trials Complement Complex Confusion Cytoplasm 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 Good Manufacturing Process Granulomatous disease Harvest Immune Immune Targeting Immune system Immunocompetent Immunosuppressive Agents Immunotherapy In Vitro Infection Injury Innate Immune Response Innate Immune System Knowledge Life Macrophage-1 Antigen Mediating Mediator Modeling Molecular Mus PRTN3 gene Pathogenesis Pathogenicity Patients Peroxidases 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 lymphocyte function associated antigen 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.

抽象的抗中性粒细胞胞质自身抗体 (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可以使大多数患者得到缓解，我们的治疗精度更像是电锯而不是手术刀。缺乏具体、有针对性的免疫疗法会使患者的免疫系统过度受损，并产生许多毒副作用。我们的该提案旨在最终推动该领域走向更精确、更有针对性的治疗方法，但潜力却小得多为了伤害。在我们之前的工作基础上，我们将尝试利用所观察到的适应性自身免疫反应 ANCA GN 作为多种方法免疫调节治疗的靶标。通过使用我们之前的开发了表位作图技术，我们将设计嵌合自身抗体受体 (CAAR) T 细胞，专门针对那些表达致病性 ANCA 抗体表位的 B 细胞。在另一种方法中，我们将分析 T 调节细胞的异质群体。在确定那些完全符合的之后抑制性，我们将尝试在体外扩大该群体并确认它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，在体外进行扩增，然后将其重新引入患者体内，以提供免疫调节作用会重新引入自身免疫耐受。利用我们充分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开发 T 调节细胞治疗的临床前模型。除了基于细胞的疗法的潜在作用外，我们还将探讨先天免疫的作用 ANCA GN 系统使用我们建立的 MPO 小鼠模型和我们开发的新模型肉芽肿性疾病。这些模型还将帮助我们识别先天免疫反应的组成部分可能适合新疗法。此外，我们将确定是否可以操纵表观遗传改变自身抗原蛋白表达的变化，这些自身抗原蛋白是驱动自身免疫过程的目标安卡 GN。这些基础研究的目的是为新药研究 (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 的特点是精度更高、毒性更小，而且可能持续时间更长。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Relevance of Combined Clinicopathologic Phenotype and Antineutrophil Cytoplasmic Autoantibody Serotype in the Diagnosis of Antineutrophil Cytoplasmic Autoantibody Vasculitis.

DOI：
10.1016/j.ekir.2022.09.011
发表时间：
2022-12
期刊：
KIDNEY INTERNATIONAL REPORTS
影响因子：
6
作者：
Alba, Marco A.;Jennette, J. Charles;Hu, Yichun;Poulton, Caroline J.;Blazek, Lauren;Derebail, Vimal K.;Falk, Ronald J.;Hogan, Susan L.
通讯作者：
Hogan, Susan L.

Should PLEX Be Used for Severe AKI and/or Pulmonary Hemorrhage in ANCA-Associated Vasculitis (AAV)? PRO.

DOI：
10.34067/kid.0006762020
发表时间：
2021-05
期刊：
Kidney360
影响因子：
0
作者：
Derebail VK
通讯作者：
Derebail VK

Malignancy risk in kidney transplant recipients exposed to immunosuppression pre-transplant for the treatment of glomerulonephritis.

肾移植受者在移植前接受免疫抑制治疗肾小球肾炎的恶性肿瘤风险。

DOI：
10.1093/ndt/gfac337
发表时间：
2023
期刊：
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association
影响因子：
0
作者：
Massicotte-Azarniouch,David;Detwiler,RandalK;Hu,Yichun;Falk,RonaldJ;Saha,ManishK;Hogan,SusanL;Derebail,VimalK
通讯作者：
Derebail,VimalK

Infections Following Kidney Transplantation After Exposure to Immunosuppression for Treatment of Glomerulonephritis.

肾移植后暴露于免疫抑制治疗肾小球肾炎后的感染。

DOI：
10.1053/j.ajkd.2023.10.016
发表时间：
2023
期刊：
American journal of kidney diseases : the official journal of the National Kidney Foundation
影响因子：
0
作者：
Massicotte-Azarniouch,David;Detwiler,RandalK;Hu,Yichun;Falk,RonaldJ;Saha,ManishK;vanDuin,David;Hogan,SusanL;Derebail,VimalK
通讯作者：
Derebail,VimalK