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）

• 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
• 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

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（NK）细胞是先天免疫系统的淋巴细胞。NK细胞保护我们 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， 感染的靶细胞。最近的实验表明，长寿命的“记忆样”NK细胞的产生，类似于 记忆淋巴细胞在适应性免疫系统，在小鼠和人类的挑战病毒感染 (such如巨细胞病毒）。这些记忆NK细胞产生了更有力的ADCC反应相比， 它们的幼稚对应物使记忆NK细胞成为增强单克隆抗体的有吸引力的候选者。 针对癌症和传染病的基于抗体的免疫疗法。然而，两个主要问题限制了 将“记忆样”NK细胞用于此类疗法：1）对潜在机制的初步理解 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 调节ADCC的网络。我们通过开发计算模型来解决上述挑战， 人类NK细胞亚群诱导的抗体应答的预测能力（从幼稚到记忆）， 小鼠通过协同地组合数据驱动和机械的计算机模型（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）与单细胞质量细胞计数术 通过飞行时间（CyTOF）和最先进的湿实验室实验，在从人获得的原代NK细胞中进行 实验对象和转基因小鼠。该提案的目的是定量描述 在人类和小鼠的不同NK细胞亚群中ADCC的潜在机制，然后使用这种定量的 因此，我们希望能够开发出更准确地反映人类情况的新型ADCC小鼠模型。 我们将追求两个目标：目标1：在人类幼稚和记忆NK细胞亚群中建模ADCC活性。目标二： 在小鼠NK细胞中建模ADCC。对差异进行定量描述的预期结果 CD 16和CD 32受体在不同NK细胞亚群中诱导ADCC的机制中存在协同作用 (na（Aim 1）将帮助我们产生更准确地识别NK细胞的改进小鼠模型， 代表由人NK细胞介导的ADCC（Aim 2）。这个独特的框架将提供科学的 社区与ADCC的小鼠模型，更准确地反映了人类的情况，一个关键的资产 用于癌症和传染病单克隆抗体治疗的临床前开发。