Development of iPSC-derived iNKT cells to promote hematopoietic engraftment
开发 iPSC 衍生的 iNKT 细胞以促进造血植入
基本信息
- 批准号:10632065
- 负责人:
- 金额:$ 19.44万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-06-01 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:AblationAdjuvantAdultAffectAllogenicAntigen PresentationB-LymphocytesBone Marrow Cell TransplantationBone Marrow TransplantationCD1d antigenCD34 geneCell LineCell TherapyCell physiologyCellsCellular immunotherapyClinicalCytotoxic T-LymphocytesDevelopmentDinoprostoneDiseaseE4BP4EngineeringEngraftmentFoundationsGene Expression ProfilingGenetic DiseasesGenetic TranscriptionGraft vs Tumor EffectGranulocyte-Macrophage Colony-Stimulating FactorHIVHematological DiseaseHematopoieticHematopoietic Stem Cell TransplantationHumanHuman Herpesvirus 4IL17 geneIL3 GeneImmuneImmune System DiseasesImmunodeficient MouseInfectionInflammationInflammatoryInterferon Type IIInterleukin-10Interleukin-13Interleukin-4Knock-inKnock-outLeftLymphomaLymphomagenesisMalignant NeoplasmsMediatingModelingMononuclearMorbidity - disease rateMusOutputPathologicPatientsPredispositionProceduresProductionPropertyProtocols documentationPublishingSignal TransductionSystemT-LymphocyteTestingTherapeuticToxic effectTransplantationTransplantation ConditioningTumor BurdenUmbilical Cord BloodUmbilical Cord Blood TransplantationZNF145 genecombatconditioningcurative treatmentscytokinedesigndifferential expressionfactor Agraft failurehematopoietic engraftmenthematopoietic transplantationhigh riskimprovedimproved outcomeinduced pluripotent stem cellinduced pluripotent stem cell technologyinfectious disease treatmentinsightleukemia relapsemonocytemortalitymouse modelnovelnovel therapeutic interventionnovel therapeuticsoverexpressionprogramsresponsesegregationsuccesstherapy designtranscription factor
项目摘要
Summary
Hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for a variety of malignancies
and other hematological disorders, and also holds promise for treatment of infectious diseases such as HIV.
However, HSCT is limited by high risks of morbidity and mortality from complications such as graft failure
(which leads to high susceptibility to lethal infections) and leukemic relapse. New strategies to improve
outcomes of hematopoietic transplantation would thus have a significant clinical impact. This project focuses
on developing invariant Natural Killer T (iNKT) cells derived from human induced pluripotent stem cells (iPSCs)
as an adjunct HSCT cellular therapy designed to promote successful hematopoietic engraftment. In recently
published preliminary studies, we showed that addition of allogeneic human CD4+ iNKT cells to human
umbilical cord blood transplants led to dramatically improved hematopoietic engraftment in immunodeficient
mice. The engraftment-promoting activity of iNKT cells was due to their interactions with cord blood
monocytes that resulted in production of several potently pro-hematopoietic factors, including the cytokines
GM-CSF and IL-3 (produced by iNKT cells), and PGE2 (produced by monocytes in response to signals from
iNKT cells). Prior studies in murine models have established that cytokine programs and functional properties
of iNKT cells are controlled by two key transcription factors, PLZF and E4BP4. How these transcription factors
influence the cytokine profiles of human iNKT cells remains unclear, and specifically, their impact on iNKT cell
production of GM-CSF and IL-3 and interactions with monocytes is not known. Aim 1 of this project proposes
to generate human iPSC-derived iNKT cells lacking or over-expressing PLZF or E4BP4. Aim 2 will determine
the impact of these transcription factors on the ability of iPSC-derived iNKT cells to promote human
hematopoietic engraftment and on graft-versus-lymphoma (GVL) activity. Through these studies we will gain
highly novel insight into the impact of PLZF and E4BP4 expression on iNKT functional properties, and we will
establish the feasibility of generating iPSC-derived iNKT cells with modified transcription factor expression
designed to stabilize specific functional programs. This will lay a foundation for designing iPSC-derived iNKT
cells that are transcriptionally tuned to promote hematopoietic engraftment without adversely affecting GVL.
总结
造血干细胞移植(HSCT)是一种治疗多种恶性肿瘤的有效方法
和其他血液疾病,并且也有望用于治疗感染性疾病如HIV。
然而,HSCT受到并发症(如移植失败)的高发病率和死亡率风险的限制
(这导致对致命感染的高度易感性)和白血病复发。新的战略,以改善
因此,造血移植的结果将具有显著的临床影响。该项目重点
开发来自人类诱导多能干细胞(iPSC)的不变自然杀伤T(iNKT)细胞
作为辅助HSCT细胞疗法,旨在促进成功的造血移植。在最近
发表的初步研究,我们表明,加入同种异体人CD 4 + iNKT细胞,
脐带血移植显著改善了免疫缺陷患者的造血植入,
小鼠iNKT细胞的移植促进活性是由于它们与脐带血的相互作用
单核细胞,导致产生几种有效的促造血因子,包括细胞因子
GM-CSF和IL-3(由iNKT细胞产生)和PGE 2(由单核细胞响应来自
iNKT细胞)。先前在小鼠模型中的研究已经确定,细胞因子程序和功能特性
iNKT细胞的增殖受两个关键转录因子PLZF和E4 BP 4控制。这些转录因子是如何
影响人iNKT细胞的细胞因子谱尚不清楚,具体而言,它们对iNKT细胞的影响
GM-CSF和IL-3的产生以及与单核细胞的相互作用尚不清楚。该项目的目标1提出
以产生缺乏或过表达PLZF或E4 BP 4的人iPSC衍生的iNKT细胞。目标2将决定
这些转录因子对iPSC衍生的iNKT细胞促进人类免疫应答的能力的影响。
造血植入和移植物抗淋巴瘤(GVL)活性。通过这些研究,
PLZF和E4 BP 4表达对iNKT功能特性的影响的高度新颖的见解,我们将
建立产生具有修饰的转录因子表达的iPSC衍生的iNKT细胞的可行性
用于稳定特定的功能程序。这将为设计iPSC衍生的iNKT奠定基础
在转录上被调节以促进造血移植而不会不利地影响GVL的细胞。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Harnessing invariant natural killer T cells to control pathological inflammation.
- DOI:10.3389/fimmu.2022.998378
- 发表时间:2022
- 期刊:
- 影响因子:7.3
- 作者:Bharadwaj, Nikhila S. S.;Gumperz, Jenny E. E.
- 通讯作者:Gumperz, Jenny E. E.
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Jenny E. Gumperz其他文献
Heterogeneous phenotypes of expression of the NKB1 natural killer cell class I receptor among individuals of different human histocompatibility leukocyte antigens types appear genetically regulated, but not linked to major histocompatibililty complex haplotype
不同人类组织相容性白细胞抗原类型个体中NKB1自然杀伤细胞I类受体表达的异质表型似乎受到遗传调节,但与主要组织相容性复合体单倍型无关
- DOI:
- 发表时间:
1996 - 期刊:
- 影响因子:15.3
- 作者:
Jenny E. Gumperz;N. Valiante;Peter Parham;Lewis L. Lanier;D. Tyan - 通讯作者:
D. Tyan
Jenny E. Gumperz的其他文献
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{{ truncateString('Jenny E. Gumperz', 18)}}的其他基金
Development of iPSC-derived iNKT cells to promote hematopoietic engraftment
开发 iPSC 衍生的 iNKT 细胞以促进造血植入
- 批准号:
10525780 - 财政年份:2022
- 资助金额:
$ 19.44万 - 项目类别:
Understanding the impact of human NKT cells on hematopoiesis
了解人类 NKT 细胞对造血的影响
- 批准号:
9096694 - 财政年份:2015
- 资助金额:
$ 19.44万 - 项目类别:
Analysis of human NKT cells in GVHD in vivo
人 NKT 细胞在体内 GVHD 中的分析
- 批准号:
8247271 - 财政年份:2012
- 资助金额:
$ 19.44万 - 项目类别:
Analysis of human NKT cells in GVHD in vivo
人 NKT 细胞在体内 GVHD 中的分析
- 批准号:
8416354 - 财政年份:2012
- 资助金额:
$ 19.44万 - 项目类别:
Functional analysis of human NKT cells and myeloid DCs within murine SCID hosts
小鼠 SCID 宿主体内人类 NKT 细胞和髓样 DC 的功能分析
- 批准号:
7356104 - 财政年份:2009
- 资助金额:
$ 19.44万 - 项目类别:
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