Modeling the influence of sex on natural killer cell networks

模拟性别对自然杀伤细胞网络的影响

基本信息

批准号：
8994014
负责人：
Catherine A Blish
金额：
$ 9.87万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-30 至 2018-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Vaccination is one of the most effective methods to prevent morbidity and mortality related to infectious diseases, yet there are many viral infections, such as Human Immunodeficiency Virus (HIV) and cytomegalovirus (CMV), for which durable, broadly cross-protective vaccines remain desperately needed. Although most of the focus in vaccine development has been on adaptive immune responses, natural killer (NK) cells are innate lymphocyte responders that rapidly and robustly kill virus-infected cells. Recent data has demonstrated that NK cells share features of adaptive immune responses-including the ability to respond more quickly and robustly upon a second challenge with the same antigen. Thus, they show great promise in establishing early control of infection in a vaccine or therapeutic setting where adaptive immune responses have proven to be too little and too late. Before this response can be elicited successfully, NK cell recognition of virus-infected cells must be understood at a detailed level. However, NK cells are a highly heterogeneous cell population, capable of a vast variety of functions and possessing a complex mosaic of surface receptors. The limits of fluorescence cytometry have prevented the simultaneous examination of all of these traits. To address this question, we propose the use of a novel technology, Cytometry by Time-Of-Flight (CyTOF). CyTOF can detect up to 40 cellular markers simultaneously, a considerable advance from the traditional fluorescence cytometry limit of 12-18. Thus, we will use CyTOF to comprehensively measure NK cell phenotype and functions during killing of virus-infected cells. We will define the specific populations of effector NK cells critical for responsesto HIV, influenza, and CMV by developing in vitro viral suppression assays in which NK cells from healthy donors recognize and kill autologous cells infected with these viruses. The highly parametric, deep profiling capabilities of CyTOF, applied to this specific, controlled interrogatio of antiviral NK cell function, will allow us to gain profound insight into which NK cells are activly recognizing and killing virus- infected cells. Results will be analyzed using a variety of complementary statistical techniques and dimensionality reduction algorithms. Once this analysis has defined specific subsets of NK cells involved in killing virus-infected cells, we will complement these findings using in vitro functional assays to define precisely how the NK cells are recognizing and killing the infected cells. These assays classically examine single receptors or functions, but will be adapted to simultaneously interrogate multiple receptors or functions in a combinatorial manner. Our innovative approach aims to understand which NK cell subsets to prime and which functions to stimulate in order to purposefully elicit an antiviral response in a vaccine or therapeutic setting. Our findings will therefore drive the development of innovative new approaches to vaccination.

描述（由申请人提供）：疫苗接种是预防与感染疾病有关的发病率和死亡率的最有效方法之一，但是有许多病毒感染，例如人类免疫缺陷病毒（HIV）和巨细胞病毒（CMV），对于耐用，耐用，耐用，迫切需要广泛的交叉保护疫苗。尽管疫苗发育中的大多数重点一直放在自适应免疫反应上，但天然杀伤（NK）细胞是先天的淋巴细胞反应者，它们迅速且迅速杀死了感染了病毒的细胞。最近的数据表明，NK细胞具有自适应免疫反应的特征，包括对使用相同抗原的第二个挑战更快，更牢固地反应的能力。因此，他们在在疫苗或治疗环境中建立对感染的早期控制方面表现出了巨大的希望，在这种情况下，自适应免疫反应已被证明太少和太晚了。在成功引起这种反应之前，NK细胞识别病毒感染的细胞必须在详细的层面上可以理解。但是，NK细胞是一种高度异质的细胞群，能够具有多种功能，并且具有复杂的表面受体镶嵌物。荧光细胞仪的限制阻止了所有这些特征的同时检查。为了解决这个问题，我们建议使用一种新技术，即飞行时间（Cytof）的细胞仪。 Cytof可以同时检测到多达40个细胞标记，这是从传统的荧光细胞仪极限为12-18的相当大的进步。因此，我们将使用Cytof在杀死感染病毒的细胞期间全面测量NK细胞表型和功能。我们将通过开发体外病毒抑制测定法，定义对反应HIV，流感和CMV至关重要的效应NK细胞的特定群体，在该测定中，来自健康供体的NK细胞识别并杀死感染了这些病毒的自体细胞。 CytoF的高度参数，深层分析能力应用于此特定的，受控的抗病毒NK细胞功能的介绍，将使我们能够深入了解哪些NK细胞可以激活和杀死病毒感染细胞。将使用各种互补统计技术和降低算法来分析结果。一旦该分析定义了参与杀死病毒感染细胞的NK细胞的特定子集，我们将使用体外功能测定法对这些发现进行补充，以精确定义NK细胞如何识别和杀死感染细胞。这些测定法经典检查单个受体或功能，但将适应以组合方式同时询问多个受体或功能。我们的创新方法旨在了解哪些NK细胞子集用于Prume以及哪些功能刺激以目的是在疫苗或治疗环境中引起抗病毒反应。因此，我们的发现将推动创新的疫苗接种新方法的发展。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Identification of the first cases of complete CD16A deficiency: Association with persistent EBV infection.

DOI：
10.1016/j.jaci.2019.11.049
发表时间：
2020-04
期刊：
The Journal of allergy and clinical immunology
影响因子：
0
作者：
Pérez-Portilla A;Moraru M;Blázquez-Moreno A;Kolb P;Bravo García-Morato M;Ranganath T;Esteso G;Gianelli C;Rodríguez-Pena R;Lozano-Rodríguez R;Torres-Canizales JM;Blish CA;Vales-Gomez M;Hengel H;Vilches C;López-Granados E;Reyburn HT
通讯作者：
Reyburn HT

CyTOF analysis identifies unusual immune cells in urine of BCG-treated bladder cancer patients.

DOI：
10.3389/fimmu.2022.970931
发表时间：
2022
期刊：
Frontiers in immunology
影响因子：
7.3
作者：
通讯作者：

Human NK Cell Diversity in Viral Infection: Ramifications of Ramification.

DOI：
10.3389/fimmu.2016.00066
发表时间：
2016
期刊：
Frontiers in immunology
影响因子：
7.3
作者：
Strauss-Albee DM;Blish CA
通讯作者：
Blish CA

NKG2A-Expressing Natural Killer Cells Dominate the Response to Autologous Lymphoblastoid Cells Infected with Epstein-Barr Virus.

DOI：
10.3389/fimmu.2016.00607
发表时间：
2016
期刊：
Frontiers in immunology
影响因子：
7.3
作者：
Hatton O;Strauss-Albee DM;Zhao NQ;Haggadone MD;Pelpola JS;Krams SM;Martinez OM;Blish CA
通讯作者：
Blish CA

Natural Killer Cell Diversity in Viral Infection: Why and How Much?