Harnessing NK cell effector function for immunotherapies

利用 NK 细胞效应功能进行免疫治疗

基本信息

  • 批准号:
    9296856
  • 负责人:
  • 金额:
    $ 25.43万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-08-18 至 2019-07-31
  • 项目状态:
    已结题

项目摘要

Natural Killer (NK) cells are a major lineage of human lymphocytes with vital functions in innate and adaptive immunity and adaptive immunity to hematologic cancers. NK cell functions are mediated by the diverse interactions of highly polymorphic HLA-A, -B, and -C molecules with equally polymorphic killer immunoglobulin- like receptors (KIR). They are complemented by the conserved interactions of HLA-E with CD94:NKG2 heterodimers. The genes encoding KIR receptors and HLA ligands segregate independently, thereby generating unique and diverse genotypes within families and populations. Phenotypically, this produces functionally distinct NK cell repertoires, a natural variation that has profound effects on the outcome of HCT. To date, there has never been an appropriate in vivo xenogeneic model for studying NK-cell development and education through HCT or for validating the adoptive transfer of human NK cells. Historically, there have been two major barriers to study human NK-cell engraftment and function: (1) human NK-cell reconstitution and survival is dependent upon common -chain cytokines IL-2, IL-7 and IL-15 that are not cross reactive between species; and (2) human NK-cell function is educated, regulated and maintained by inhibitory receptor engagement with MHC class I molecules that are also not cross-reactive between species. We have now overcome the cytokine and MHC class I barrier by utilizing a cutting-edge adeno-associated virus (AAV) vector-mediated gene delivery approach to transduce genes encoding HLA-A, -B, -C and –E polypeptides, as well as certain human cytokines, to highly immunodeficient NSG mice that lack mouse-derived 2- microglobulin, named NSG-B2M-/- mice. In Specific Aim (SA)1 we will establish human immune system (HIS) mice expressing select human cytokines and HLA-A*02 and/or HLA-E. The cytokines IL-2, IL-3, IL-6, IL-7, IL- 15 and GM-CSF will promote development of human NK cells along with human T cells, B cells, myeloid macrophages and DCs. We will apply a 42-plex mass cytometry antibody panel to closely map lymphocyte reconstitution following HCT at an unprecedented resolution. NK cell development, education and function will be studied longitudinally over a range of 20 weeks. In SA2 we will infect HIS mice with luciferase-labeled tumor target cells in order to evaluate the impact of NK cell education on anti-tumor activity and outcome of HCT. We will compare anti-tumor function of NK cells from HIS mice by mass cytometry as well as tumor burden by bioluminescence imaging. Our HIS mouse model will provide a definitive answer on whether HLA-E can directly educate CD94:NKG2A+ human NK cells and how this education impacts their capacity to respond to circulating tumors. In SA2, we will also measure the in vivo effects of CMV infection (and reactivation) on the education of adaptive NK cells and their enhanced anti-tumor response. With the ultimate goal of developing HIS mice expressing human cytokines along with complex HLA class I haplotypes, we will be able to effectively harness NK cell effector for treatment of hematologic cancers.
自然杀伤(NK)细胞是人类淋巴细胞的主要谱系,在先天和适应性免疫中具有重要功能。 免疫和获得性免疫。NK细胞的功能是由多种 高度多态性的HLA-A、-B和-C分子与同样多态性的杀伤免疫球蛋白的相互作用, 类受体(KIR)。它们通过HLA-E与CD 94:NKG 2的保守相互作用得到补充 异二聚体。编码KIR受体和HLA配体的基因独立分离,从而 在家庭和群体中产生独特和多样的基因型。从表型上看, 功能不同的NK细胞库,这是一种对HCT结果具有深远影响的自然变异。到 迄今为止,还没有合适的体内异种模型用于研究NK细胞发育, 通过HCT的教育或用于验证人NK细胞的过继转移。历史上, 研究人NK细胞移植和功能的两个主要障碍:(1)人NK细胞重建和 存活依赖于共同的β-链细胞因子IL-2、IL-7和IL-15,它们在细胞因子之间不交叉反应。 人NK细胞功能受抑制性受体的训练、调节和维持 与MHC I类分子接合,这些分子在物种之间也没有交叉反应性。我们现在已经 利用最先进的腺相关病毒(AAV)克服细胞因子和MHC I类障碍 载体介导的基因递送方法,其将编码HLA-A、-B、-C和-E多肽的HLA-A基因,如 以及某些人细胞因子,对缺乏小鼠源性β 2受体的高度免疫缺陷NSG小鼠, 微球蛋白,命名为NSG-B2 M-/-小鼠。在特定目标(SA)1中,我们将建立人类免疫系统(HIS) 表达选择的人细胞因子和HLA-A*02和/或HLA-E的小鼠。细胞因子IL-2、IL-3、IL-6、IL-7、IL-10、IL-11、IL-12、IL-13、IL-14、IL-16、IL-17、IL-18、IL-19、IL- 15和GM-CSF将促进人NK细胞与人T细胞、B细胞、髓样细胞、淋巴细胞和淋巴细胞一起沿着发育。 巨噬细胞和DC。我们将应用42重流式细胞术抗体板来密切定位淋巴细胞 在HCT后以前所未有的分辨率重建。NK细胞的发育、教育和功能将 在20周的时间范围内进行纵向研究。在SA 2中,我们将用酶标记的肿瘤感染HIS小鼠 靶细胞,以评估NK细胞教育对抗肿瘤活性和HCT结果的影响。我们 将通过质谱细胞术比较来自HIS小鼠的NK细胞的抗肿瘤功能,以及通过流式细胞术比较肿瘤负荷。 生物发光成像我们的HIS小鼠模型将提供一个明确的答案,HLA-E是否可以 直接教育CD 94:NKG 2A+人NK细胞,以及这种教育如何影响他们应对 循环肿瘤在SA 2中,我们还将测量CMV感染(和再活化)对细胞的体内影响。 适应性NK细胞及其增强的抗肿瘤反应的教育。最终目标是发展 HIS小鼠表达人类细胞因子沿着复杂的HLA I类单倍型,我们将能够有效地 利用NK细胞效应子治疗血液癌症。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Amir Horowitz其他文献

Amir Horowitz的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Amir Horowitz', 18)}}的其他基金

HLA-E and NKG2A define a novel immune checkpoint axis in non-muscle-invasive bladder cancer
HLA-E 和 NKG2A 定义了非肌层浸润性膀胱癌的新型免疫检查点轴
  • 批准号:
    10587009
  • 财政年份:
    2023
  • 资助金额:
    $ 25.43万
  • 项目类别:
Identifying novel resistance mechanisms in non-muscle invasive bladder cancer treated with Bacillus Calmette-Guerin (BCG)
识别卡介苗 (BCG) 治疗的非肌层浸润性膀胱癌的新耐药机制
  • 批准号:
    10742368
  • 财政年份:
    2023
  • 资助金额:
    $ 25.43万
  • 项目类别:

相似海外基金

Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
  • 批准号:
    MR/S03398X/2
  • 财政年份:
    2024
  • 资助金额:
    $ 25.43万
  • 项目类别:
    Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
  • 批准号:
    EP/Y001486/1
  • 财政年份:
    2024
  • 资助金额:
    $ 25.43万
  • 项目类别:
    Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
  • 批准号:
    2338423
  • 财政年份:
    2024
  • 资助金额:
    $ 25.43万
  • 项目类别:
    Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
  • 批准号:
    MR/X03657X/1
  • 财政年份:
    2024
  • 资助金额:
    $ 25.43万
  • 项目类别:
    Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
  • 批准号:
    2348066
  • 财政年份:
    2024
  • 资助金额:
    $ 25.43万
  • 项目类别:
    Standard Grant
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
  • 批准号:
    2341402
  • 财政年份:
    2024
  • 资助金额:
    $ 25.43万
  • 项目类别:
    Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
  • 批准号:
    AH/Z505481/1
  • 财政年份:
    2024
  • 资助金额:
    $ 25.43万
  • 项目类别:
    Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10107647
  • 财政年份:
    2024
  • 资助金额:
    $ 25.43万
  • 项目类别:
    EU-Funded
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10106221
  • 财政年份:
    2024
  • 资助金额:
    $ 25.43万
  • 项目类别:
    EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
  • 批准号:
    AH/Z505341/1
  • 财政年份:
    2024
  • 资助金额:
    $ 25.43万
  • 项目类别:
    Research Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了