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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：
10764466
负责人：
Jayajit Das
金额：
$ 4.08万
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 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10764466
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.

项目概述：自然杀伤细胞（NK）是先天免疫系统的淋巴细胞。NK细胞保护我们