NK Cells in GVHD and GVT
GVHD 和 GVT 中的 NK 细胞
基本信息
- 批准号:7673379
- 负责人:
- 金额:$ 29.49万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-08-11 至 2013-05-31
- 项目状态:已结题
- 来源:
- 关键词:Animal ModelAnimalsApoptosisBiologicalBiologyBioluminescenceCell TransplantationCell surfaceCellsCellular biologyClinicComplexCytolysisDissectionEffector CellEventExcisionFluorescenceFunctional disorderGastrointestinal tract structureGoalsGraft vs Tumor EffectHematologic NeoplasmsHematopoieticHistocompatibilityHomologous TransplantationHumanImageImmuneImmunobiologyInduction of ApoptosisInfiltrationLifeLigandsLightLiverLocationLongevityLuciferasesLymphocyteLymphoidLymphoid TissueMalignant NeoplasmsMediatingModelingNatural Killer CellsNodalOrganPatientsPopulationProliferatingProteinsReactionRecovery of FunctionResidual TumorsRiskRoleSiteSkinSourceStructureT-Cell ActivationT-LymphocyteTimeTissue GraftsTissuesTransgenic MiceTranslatingTransplantationTumor Tissuebasecancer cellcellular imagingclinically relevantdisorder controldisorder riskeffective therapyexperiencegraft vs host diseaseimage processingimprovedinsightinterestkiller T cellmigrationneoplastic cellnovelpublic health relevancereconstitutionresponsesuccesstraffickingtumor
项目摘要
DESCRIPTION (provided by applicant): Hematopoietic cell transplantation (HCT) is an effective therapy for patients with a broad range of hematologic malignancies. The benefits of HCT are in large part derived from the immunological recognition of malignant cells resulting in their removal termed the graft vs. tumor (GVT) effect clearly demonstrating the impact of immune based control of malignancy. The success of HCT is limited by the risk of graft vs. host disease (GVHD) which results in tissue specific immune destruction. In this proposal we will focus on natural killer (NK) cells which have known anti-tumor capabilities yet do not cause GVHD. We will utilize a novel bioluminescent imaging (BLI) strategy to probe GVHD and GVT reactions. NK and T cell populations of interest will be isolated from a novel luciferase (luc) transgenic mouse and emit light. Trafficking and survival of luc+ cells can be followed in real time with high precision and sensitivity. BLI will be utilized to identify the major sites of GVHD induction and explore the impact of NK cells on GVHD induction building upon our extensive previous experience of T cell imaging. These studies will direct more probing analysis of the infiltrating tissues and cell populations. We have shown that GVHD develops through the spatial and temporal migration of lymphocytes to key anatomical sites whereby alloreactive cells proliferate and upregulate other cell surface molecules required for entry into GVHD target organs. We will evaluate the impact of NK cells on T cell trafficking and survival as well as explore NK cell trafficking to examine underlying mechanisms of why this cell population does not result in GVHD. Our hypothesis is that NK cells are capable of modulating the proliferation and survival of alloreactive T cells and can induce apoptosis of activated alloreactive T cells at lymphoid tissue sites. We further hypothesize that alloreactive T cells up-regulate NKG2D ligand expression which is recognized by NK cells via NKG2D resulting in apoptosis induction. We will further evaluate the specific populations of NK cells capable of proliferating and trafficking to tumor sites and explore phenotypic and functional immune reconstitution following transplantation in the presence and absence of NK cells. The goals of this Project are to gain greater biological insight into NK cell biology in the context of the clinically important yet complex GVHD and GVT reactions and to explore the role of NK cells in these reactions. We believe these studies will reveal basic biological insights into the pathophysiology of important immune reactions, the interplay between immune effector and regulatory lymphocytes and strategies which may be translated to the clinic.
PUBLIC HEALTH RELEVANCE The goal of this proposal is to further our understanding of the immunobiology of hematopoietic cell transplantation through the study of natural killer cells which have the unique capabilities of improving anti-tumor effects without causing graft vs host disease. We hope to understand the mechanisms of improved graft vs. tumor effects without graft vs host disease using novel bioluminescent based imaging strategies to explore the temporal and spatial events in natural killer cell biology in models of these events.
描述(由申请人提供):造血细胞移植(HCT)是一种有效的治疗多种血液系统恶性肿瘤的方法。HCT的好处在很大程度上来自于对恶性细胞的免疫识别,从而将其清除,称为移植物抗肿瘤(GVT)效应,这清楚地证明了基于免疫控制恶性肿瘤的影响。HCT的成功受到移植物抗宿主病(GVHD)风险的限制,GVHD会导致组织特异性免疫破坏。在本研究中,我们将重点研究已知具有抗肿瘤能力但不会引起GVHD的自然杀伤细胞(NK)。我们将利用一种新的生物发光成像(BLI)策略来探测GVHD和GVT反应。NK细胞群和T细胞群将从一种新型荧光素酶转基因小鼠中分离出来并发光。可以实时跟踪luc+细胞的转运和存活情况,具有较高的精度和灵敏度。BLI将用于确定GVHD诱导的主要位点,并在我们之前广泛的T细胞成像经验的基础上探索NK细胞对GVHD诱导的影响。这些研究将指导对浸润组织和细胞群进行更深入的分析。我们已经证明,GVHD是通过淋巴细胞在空间和时间上迁移到关键解剖部位而发展起来的,在这种情况下,同种异体反应性细胞增殖并上调进入GVHD靶器官所需的其他细胞表面分子。我们将评估NK细胞对T细胞运输和存活的影响,并探索NK细胞运输,以检查为什么这种细胞群不会导致GVHD的潜在机制。我们的假设是NK细胞能够调节同种异体反应性T细胞的增殖和存活,并能诱导淋巴组织部位活化的同种异体反应性T细胞凋亡。我们进一步假设,同种异体反应性T细胞上调NKG2D配体的表达,NK细胞通过NKG2D识别NKG2D配体,从而诱导细胞凋亡。我们将进一步评估能够增殖和运输到肿瘤部位的NK细胞的特定群体,并探索在NK细胞存在和不存在的情况下移植后的表型和功能免疫重建。该项目的目标是在临床上重要但复杂的GVHD和GVT反应的背景下获得更大的NK细胞生物学见解,并探索NK细胞在这些反应中的作用。我们相信这些研究将揭示重要免疫反应的病理生理学,免疫效应细胞和调节淋巴细胞之间的相互作用以及可能转化为临床的策略的基本生物学见解。
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 }}
Robert S Negrin其他文献
Treatment of donors with liposomal alpha-galactosylceramide results in the in vivo expansion of invariant natural killer T cells and reduced incidence of acute graft versus host disease
用脂质体 α-半乳糖神经酰胺治疗供体可导致不变自然杀伤 T 细胞体内扩增,并降低急性移植物抗宿主病的发生率
- DOI:
- 发表时间:
2017 - 期刊:
- 影响因子:0
- 作者:
Toshihito Hirai;Federico Simonetta;Kristina Mass-Bauer;Jeanette Baker;Mustafa Tukoz;Maite Alvarez;Melissa Mavers;Robert S Negrin - 通讯作者:
Robert S Negrin
Robert S Negrin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('Robert S Negrin', 18)}}的其他基金
Regulatory T cells in allogeneic transplantation
同种异体移植中的调节性T细胞
- 批准号:
9065603 - 财政年份:2012
- 资助金额:
$ 29.49万 - 项目类别:
Regulatory T cells in allogeneic transplantation
同种异体移植中的调节性T细胞
- 批准号:
8903997 - 财政年份:2012
- 资助金额:
$ 29.49万 - 项目类别:
Regulatory T cells in allogeneic transplantation
同种异体移植中的调节性T细胞
- 批准号:
8534275 - 财政年份:2012
- 资助金额:
$ 29.49万 - 项目类别:
Regulatory T cells in allogeneic transplantation
同种异体移植中的调节性T细胞
- 批准号:
8701379 - 财政年份:2012
- 资助金额:
$ 29.49万 - 项目类别:
Regulatory T cells in allogeneic transplantation
同种异体移植中的调节性T细胞
- 批准号:
8343992 - 财政年份:2012
- 资助金额:
$ 29.49万 - 项目类别:
Regulatory T Cells in Allogeneic Transplantation
同种异体移植中的调节性 T 细胞
- 批准号:
7939868 - 财政年份:2009
- 资助金额:
$ 29.49万 - 项目类别:
Regulatory T Cells in Allogeneic Transplantation
同种异体移植中的调节性 T 细胞
- 批准号:
7855234 - 财政年份:2009
- 资助金额:
$ 29.49万 - 项目类别:
相似海外基金
The earliest exploration of land by animals: from trace fossils to numerical analyses
动物对陆地的最早探索:从痕迹化石到数值分析
- 批准号:
EP/Z000920/1 - 财政年份:2025
- 资助金额:
$ 29.49万 - 项目类别:
Fellowship
Animals and geopolitics in South Asian borderlands
南亚边境地区的动物和地缘政治
- 批准号:
FT230100276 - 财政年份:2024
- 资助金额:
$ 29.49万 - 项目类别:
ARC Future Fellowships
The function of the RNA methylome in animals
RNA甲基化组在动物中的功能
- 批准号:
MR/X024261/1 - 财政年份:2024
- 资助金额:
$ 29.49万 - 项目类别:
Fellowship
Ecological and phylogenomic insights into infectious diseases in animals
对动物传染病的生态学和系统发育学见解
- 批准号:
DE240100388 - 财政年份:2024
- 资助金额:
$ 29.49万 - 项目类别:
Discovery Early Career Researcher Award
Zootropolis: Multi-species archaeological, ecological and historical approaches to animals in Medieval urban Scotland
Zootropolis:苏格兰中世纪城市动物的多物种考古、生态和历史方法
- 批准号:
2889694 - 财政年份:2023
- 资助金额:
$ 29.49万 - 项目类别:
Studentship
Using novel modelling approaches to investigate the evolution of symmetry in early animals.
使用新颖的建模方法来研究早期动物的对称性进化。
- 批准号:
2842926 - 财政年份:2023
- 资助金额:
$ 29.49万 - 项目类别:
Studentship
Study of human late fetal lung tissue and 3D in vitro organoids to replace and reduce animals in lung developmental research
研究人类晚期胎儿肺组织和 3D 体外类器官在肺发育研究中替代和减少动物
- 批准号:
NC/X001644/1 - 财政年份:2023
- 资助金额:
$ 29.49万 - 项目类别:
Training Grant
RUI: Unilateral Lasing in Underwater Animals
RUI:水下动物的单侧激光攻击
- 批准号:
2337595 - 财政年份:2023
- 资助金额:
$ 29.49万 - 项目类别:
Continuing Grant
RUI:OSIB:The effects of high disease risk on uninfected animals
RUI:OSIB:高疾病风险对未感染动物的影响
- 批准号:
2232190 - 财政年份:2023
- 资助金额:
$ 29.49万 - 项目类别:
Continuing Grant
A method for identifying taxonomy of plants and animals in metagenomic samples
一种识别宏基因组样本中植物和动物分类的方法
- 批准号:
23K17514 - 财政年份:2023
- 资助金额:
$ 29.49万 - 项目类别:
Grant-in-Aid for Challenging Research (Exploratory)