The immune regulation of macrophage antibody dependent cellular phagocytosis

巨噬细胞抗体依赖性细胞吞噬作用的免疫调节

基本信息

批准号：
10213585
负责人：
Adam David Hoppe
金额：
$ 37.02万
依托单位：
SOUTH DAKOTA STATE 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：
2020-07-10 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10213585
关键词：
Actins Adoptive Transfer Agonist Antibodies Autoimmune Diseases B-Lymphocytes Binding Biological Assay Bone Marrow CCND1 gene CD47 gene CD8B1 gene CDW52 gene CRISPR screen Cells Clustered Regularly Interspaced Short Palindromic Repeats Complex Data Data Set Dependence Disease remission Environment Gene Expression Gene Expression Profiling Gene Expression Regulation Genes Genetic Transcription Goals Human IL4 gene Immune Immunocompetent Immunoglobulin G Immunologics Immunosuppression Infection Inflammatory Interferon Type II Interferons Intervention Knock-out Ligands Lymphocyte Lymphoma Macrophage Activation Malignant - descriptor Malignant Neoplasms Mediating Membrane Metabolic Methods Microscopy Mission Modeling Molecular Monoclonal Antibodies Monoclonal Antibody CD20 Monoclonal Antibody Therapy Mus Myeloid Cells PTPNS1 gene Pathway interactions Patients Peripheral Blood Mononuclear Cell Pharmacotherapy Public Health Receptor Signaling Regulation Regulatory T-Lymphocyte Signal Transduction Spleen Stimulator of Interferon Genes Surface System Systems Analysis Systems Biology T-Lymphocyte Testing Therapeutic Therapeutic Effect Therapeutic Monoclonal Antibodies Therapeutic antibodies Translating Translations United States National Institutes of Health Variant Work anti-CD20 antibody-dependent cellular phagocytosis base clinically relevant cytokine defined contribution design effective therapy gene function human tissue humanized mouse immune function immunoregulation improved in vivo in vivo Model inhibiting antibody innovation macrophage mouse model novel patient response programs receptor receptor expression receptor function response rituximab screening therapeutic target tissue repair transcriptome sequencing transcriptomics whole genome

项目摘要

Project Summary The killing of target cells by therapeutic antibodies is expanding the effective treatment options for a wide range of autoimmune diseases and cancers. Mounting evidence from mouse models, humanized mouse systems and the analysis of human tissues, indicates that macrophages are principal effectors of therapeutic antibodies, mediating the destruction of infected, malignant and immunologically aberrant cells. Fcγ receptors (FcR) on the surface of macrophages bind target-cell associated monoclonal IgG class antibodies (mAbs) to initiate antibody-dependent cellular phagocytosis (ADCP) and killing of the target cell. Patient responses to mAb therapies can vary from complete remission to minimal therapeutic effect. One poorly explored possibility is that the variability of the ADCP response is its dependence on macrophage polarization under the influence of immune modulation. Specifically, immunosuppressive environments alter macrophage polarization leading to ineffective ADCP. Conversely, stimulators of interferon genes agonists (STINGa), acting through type 1 interferons (IFN-1) can dramatically potentiate ADCP and overcome immunosuppression. Our overarching goal is to elucidate the mechanistic pathways by which macrophage activation controls FcR function and ADCP using a systems biology approach across in vivo transcriptomics and whole genome CRISPR screens. Identified gene-function relationships for ADCP will be validated in a novel vivo model and translated to human macrophages and therapeutic antibodies. We hypothesize that ADCP is regulated across major axes of macrophage polarization (M0, M1(IFNγ/LPS), M(IFN-1/STING), M2(IL4/13) and M(S)) by gene-expression changes of yet undefined genes that modulate the A:I ratios of FcRs, their signaling machinery and innate cellular recognition receptors. Our proposal has two innovative aims that will vastly expand understanding of the regulation FcR-dependent ADCP. In Aim 1, we will elucidate the macrophage genes contributing to differential FcR function and ADCP across M1, M(IFN-1/STING), M2 and M(S). This aim takes advantage of a new CRISPR-based whole genome screening strategy to identify genes that promote and inhibit ADCP in primary derived macrophages. Aim 2 will delineate macrophage gene regulation supporting FcR function and ADCP in vivo. Here we will translate findings from patient data and the CRISPR screen from Aim 1 to define regulators of ADCP in vivo. Both aims will focus on clinically relevant anti-B cell (Rituximab) and anti-T cell (CAMPATH) antibodies, and will generate findings that extend our understanding of Fc-dependent killing mechanism of ADCP.

项目概要治疗性抗体杀死靶细胞正在扩大有效治疗选择来自小鼠模型、人源化小鼠的越来越多的证据。系统和人体组织的分析表明巨噬细胞是治疗的主要效应器抗体，介导破坏受感染的、恶性的和免疫异常的细胞。巨噬细胞表面的 (FcR) 结合靶细胞相关的单克隆 IgG 类抗体 (mAb) 启动抗体依赖性细胞吞噬作用 (ADCP) 并杀死患者的靶细胞反应。 mAb 疗法的范围从完全缓解到最小治疗效果（一种尚未充分探索的可能性）。 ADCP 反应的可变性取决于其在影响下的巨噬细胞极化具体来说，免疫抑制环境改变巨噬细胞极化主导。离线无效的 ADCP，干扰素基因激动剂 (STINGa) 的刺激剂，通过 1 型起作用。干扰素 (IFN-1) 可以显着增强 ADCP 并克服免疫抑制。我们的首要目标是阐明巨噬细胞激活控制 FcR 的机制途径使用跨体内转录组学和全基因组的系统生物学方法进行功能和 ADCP CRISPR 筛选。已确定的 ADCP 基因功能关系将在新型体内模型中得到验证。转化为人类巨噬细胞和治疗性抗体时，我们一直在努力解决 ADCP 受到跨领域监管的问题。巨噬细胞极化的主轴（M0、M1(IFNγ/LPS)、M(IFN-1/STING)、M2(IL4/13) 和 M(S)）调节 FcR 的 A:I 比率及其信号机制的尚未定义的基因的基因表达变化我们的提案有两个创新目标，将大大扩展。了解 FcR 依赖性 ADCP 的调节在目标 1 中，我们将阐明巨噬细胞基因。有助于 M1、M(IFN-1/STING)、M2 和 M(S) 之间的差异 FcR 功能和 ADCP。利用基于 CRISPR 的新全基因组筛选策略来识别促进和抑制的基因初级衍生巨噬细胞中的 ADCP 目标 2 将描述支持 FcR 的巨噬细胞基因调控。在这里，我们将翻译来自 Aim 的患者数据和 CRISPR 筛选的发现。 1 定义体内 ADCP 的调节因子。这两个目标都将集中于临床相关的抗 B 细胞（利妥昔单抗）和抗 T 细胞 (CAMPATH) 抗体，并将产生扩展我们对 Fc 依赖性的理解的发现 ADCP的杀伤机制。