Modeling Antibody-induced Immune Responses by NK cells in Mice and Humans (Resubmission 1)

模拟小鼠和人类 NK 细胞抗体诱导的免疫反应（重新提交 1）

基本信息

批准号：
10328950
负责人：
Jayajit Das
金额：
$ 50.52万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
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：
2020-02-21 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10328950
关键词：
Activated Natural Killer Cell Adaptive Immune System Address Antibodies Antibody Response CD32 Antigens CRISPR/Cas technology Cancer Patient Cells Chemical Engineering Communicable Diseases Communities Computer Models Cytomegalovirus Cytometry Data Development Dimensions FCGR2B gene FCGR3B gene Generations Genes Genetically Engineered Mouse Goals Human Human Engineering Immune response Immunooncology Immunotherapy Information Theory Innate Immune System Kinetics Lymphocyte Malignant Neoplasms Measurement Mediating Memory Modeling Molecular Monoclonal Antibodies Murid herpesvirus 1 Mus Natural Killer Cells Nonlinear Dynamics Outcome Physics Proteins Public Health Scheme Signal Pathway Signal Transduction T memory cell Techniques Therapeutic Therapeutic Monoclonal Antibodies Time Viral Virus Diseases adaptive immunity antibody-dependent cell cytotoxicity cancer therapy experimental study gain of function human subject improved in silico innovation interest laboratory experiment mouse model novel phase I trial preclinical development receptor reconstruction response rituximab statistics synergism time interval tumor

项目摘要

Project Summary: Natural Killer (NK) cells are lymphocytes of the innate immune system. NK cells defend us by inducing antibody-dependent cell mediated cytotoxicity (ADCC) where NK cells lyse antibody coated virally- infected target cells. Recent experiments showed generation of long-lived “memory-like” NK cells, similar to memory lymphocytes in the adaptive immune system, in mouse and humans challenged by viral infections (such as cytomegalovirus). These memory NK cells generated a more vigorous ADCC response compared to their naïve counterparts which make the memory NK cells an attractive candidate for augmenting monoclonal antibody based immunotherapies against cancer and infectious disease. However, two major issues limit the use of “memory-like” NK cells for such therapies: 1) A rudimentary understanding of mechanisms underlying NK cell-mediated ADCC is lacking; and 2) humans and mice show key differences in the NK cell signaling networks, which regulate ADCC. We address the above challenges by developing computational models with predictive powers for antibody responses induced by NK cell subsets (from naïve to memory) in humans and mice by synergistically combining data-driven and mechanistic in silico models (rooted in statistical physics, nonlinear dynamics, information theory, statistics, and chemical engineering) with single cell mass cytometry by time of flight (CyTOF) and state-of-the-art wet lab experiments in primary NK cells obtained from human subjects and genetically modified mice. The objective of the proposal is to quantitatively characterize mechanisms underlying ADCC in diverse NK cell subsets in humans and mice and then use this quantitative understanding to develop novel mouse models of ADCC that reflect the situation in humans more accurately. We will pursue two aims: Aim 1: Modeling ADCC activity in human naïve and memory NK cell subsets. Aim 2: Modeling ADCC in mouse NK cells. The expected outcome of quantitative characterization of the differences and synergies in mechanisms of ADCC induced by CD16 and CD32 receptors in different NK cell subsets (naïve to memory primary NK cells) (Aim 1) will help us generate improved mouse models that more accurately represent ADCC mediated by human NK cells (Aim 2). This unique framework will provide the scientific community with a mouse model for ADCC that more accurately reflects the situation in humans, a critical asset for pre-clinical development of monoclonal antibody therapeutics for cancer and infectious diseases.

项目摘要：自然杀伤 (NK) 细胞是先天免疫系统的淋巴细胞，可保护我们。通过诱导抗体依赖性细胞介导的细胞毒性（ADCC），其中 NK 细胞裂解病毒包被的抗体最近的实验表明，会产生长寿的“记忆样”NK 细胞，类似于受到病毒感染的小鼠和人类的适应性免疫系统中的记忆淋巴细胞（例如巨细胞病毒）。与 NK 细胞相比，这些记忆 NK 细胞产生了更强烈的 ADCC 反应。他们的天真贡献使记忆 NK 细胞成为增强单克隆抗体的有吸引力的候选者然而，基于抗体的癌症和传染病免疫疗法有两个主要问题限制。使用“记忆样”NK 细胞进行此类疗法：1）对潜在机制的初步了解缺乏 NK 细胞介导的 ADCC；2) 人类和小鼠在 NK 细胞信号传导方面表现出关键差异网络，它监管 ADCC，我们通过开发计算模型来解决上述挑战。对人类 NK 细胞亚群（从幼稚到记忆）诱导的抗体反应的预测能力通过协同结合数据驱动和机械模型（植根于统计物理学，非线性动力学、信息论、统计学和化学工程）与单细胞质量流式细胞术通过飞行时间 (CyTOF) 和最先进的湿实验室实验，对从人类获得的原代 NK 细胞进行实验该提案的目的是定量表征受试者和转基因小鼠。人类和小鼠不同 NK 细胞亚群中 ADCC 的潜在机制，然后使用该定量了解开发新的 ADCC 小鼠模型，以更准确地反映人类的情况。我们将追求两个目标：目标 1：模拟人类初始和记忆 NK 细胞亚群的 ADCC 活性目标 2：小鼠 NK 细胞 ADCC 建模差异定量表征的预期结果。不同NK细胞亚群中CD16和CD32受体诱导ADCC的机制及协同作用（对记忆原代 NK 细胞天真无邪）（目标 1）将帮助我们生成改进的小鼠模型，更准确地由人类 NK 细胞介导的 ADCC（目标 2）这一独特的框架将提供科学依据。社区拥有用于 ADCC 的小鼠模型，可以更准确地反映人类的情况，这是一项重要资产用于癌症和传染病的单克隆抗体疗法的临床前开发。