Novel humanized mouse model of mucosal immunity
新型人源化小鼠粘膜免疫模型
基本信息
- 批准号:10591854
- 负责人:
- 金额:$ 29.16万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-01-01 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:2019-nCoVAddressAdjuvantAllergensAntibodiesAntigensB-Cell ActivationB-LymphocytesBiologicalBloodBone MarrowBronchiCD34 geneCell CommunicationCell physiologyCellsClinicClustered Regularly Interspaced Short Palindromic RepeatsColonCredentialingDendritic CellsDevelopmentDiseaseEngraftmentEnvironmentEpithelial CellsEpitheliumExtrinsic asthmaFLT3 geneFibroblastsFluMistFormulationFutureGenerationsGeneticGenetic EngineeringHIV InfectionsHelper-Inducer T-LymphocyteHematopoieticHematopoietic stem cellsHomeostasisHumanHypersensitivityIL6 geneIL7R geneImmuneImmune responseImmune systemImmunodeficient MouseImmunofluorescence ImmunologicImmunotherapyIn VitroInfectionInflammationInflammatoryInnate Immune ResponseInterferon Type IInterleukin-6InterleukinsKnock-inKnock-in MouseKnockout MiceLiverLungLymphoidLymphoid TissueMacrophageMacrophage Colony-Stimulating FactorMalignant NeoplasmsMeasuresModelingMucosal Immune SystemMucosal ImmunityMucous MembraneMusMyeloid CellsNational Institute of Allergy and Infectious DiseaseNatural regenerationPeripheral Blood Mononuclear CellPhenotypePlasma CellsPlayPopulationPre-Clinical ModelPropertyProteinsResearchRespiratory Tract InfectionsSignal PathwaySignal TransductionSmooth Muscle MyocytesSourceSpleenStainsStem Cell FactorStromal CellsStructureSystemSystemic infectionT cell responseT-LymphocyteTSLP geneTestingThymic TissueTissuesTransgenic OrganismsTransplantationUnited States National Institutes of HealthVaccine AntigenVaccinesVirusadaptive immune responseadaptive immunityairway epitheliumantigen-specific T cellsbronchial epitheliumcell motilitycell regenerationcell typecross reactivitycytokineenzyme linked immunospot assayepithelial stem cellfetalgenetic approachhuman stem cellshumanized mouseimmune functionimprovedin vivoinfluenza infectioninfluenza virus vaccineinfluenzaviruslung injurymonocytemouse developmentmouse modelmucosal sitemucosal vaccinenext generationnoveloverexpressionpermissivenessreceptorrespiratory colonizationrespiratory smooth musclerespiratory virusresponsetissue injurytranslational immunologyvaccine development
项目摘要
PROJECT SUMMARY
Although humanized mice have been successfully used for in vivo studies of HIV infection, cancer and
immunotherapies, human naïve and adaptive immune responses remain suboptimal, with limited cross-reactivity
between murine and human cytokines considered as a key contributing factor. As a result, the human mucosal
immune system is not fully developed, and several components are missing, including the presence of human
lung epithelial cells in their natural lung environment. To address these research gaps, we propose a combined
genetic and cellular editing approach to develop the next generation of humanized mice for studies of human
mucosal immunity. Our approach is structured in two aims: in Aim 1, we will construct and credential hNSGF-
SGM3-IL6-TSLP-TSLPR mice for human immune cell development. We will generate mice expressing a
complete human TSLP receptor and examine engraftment with human hematopoietic progenitor cells (HPCs)
by measuring cellular composition of immune cells in the bone marrow, spleen, gut, airways, lungs, and blood.
To examine human immune function, we will use a mucosal formulation of influenza vaccine (Flumist) as an
immune trigger and antigen source as we have done in the past and analyze cytokine responses in the blood
and spleen; human cell migration to mucosal sites, spleen, and bone marrow; and induction of vaccine antigen-
specific T and B cells in the spleen. In Aim 2, we will construct and credential humanized airway epithelium in
hNSGF-SGM3-IL6-TSLP-TSLPR mice. We will examine the development of human airway epithelium upon
transplant of human bronchial epithelial progenitor cells in NSGF-SGM3-IL6-TSLP-TSLPR mice (humanized or
not with HPCs from the same donor) by tissue immunofluorescence staining of human-specific targets including
HLA class I. To establish the functionality of human airway epithelial cells, we will challenge mice with live
influenza virus and measure the induction of species-specific alarmins including IL-33; type I interferon signature
in human epithelial cells as a measure of their functionality in vivo, as well as tissue composition and attraction
of human immune cells to human airway epithelium. Our hypothesis is that a complete TSLP signaling pathway
and human epithelial cells will improve human mucosal immunity in humanized mice by facilitating the crosstalk
between stromal cells and immune cells. This model can then be used for i. mucosal vaccine development, and
ii. studies of other respiratory viruses including SARS-CoV-2, which requires human-specific receptors to
establish infection. Thus, once credentialed, our model will lay the groundwork for future mechanistic studies of
mucosal immunity in vivo in the context of genetically variable donors as well as enable studies of mucosal
adjuvants, allergens, vaccines, and biologicals.
项目摘要
尽管人源化小鼠已成功用于HIV感染、癌症和肿瘤的体内研究,
免疫疗法、人类初始免疫应答和适应性免疫应答仍不理想,交叉反应性有限
鼠和人细胞因子之间的差异被认为是一个关键的促成因素。因此,人体粘膜
免疫系统没有完全发育,缺少几个组成部分,包括人
肺上皮细胞在其自然肺环境中。为了解决这些研究差距,我们提出了一个综合的
基因和细胞编辑方法开发下一代人源化小鼠用于人类研究
粘膜免疫我们的方法有两个目标:在目标1中,我们将构建和认证hNSGF-
用于人免疫细胞发育的SGM 3-IL 6-TSLP-TSLPR小鼠。我们将产生表达一种
完整的人TSLP受体并检查与人造血祖细胞(HPC)的植入
通过测量骨髓、脾脏、肠道、呼吸道、肺和血液中免疫细胞的细胞组成。
为了检查人类免疫功能,我们将使用流感疫苗(Flumist)的粘膜制剂作为免疫调节剂。
免疫触发物和抗原来源,并分析血液中的细胞因子反应
和脾;人细胞迁移到粘膜部位、脾和骨髓;以及疫苗抗原的诱导-
脾脏中的特异性T和B细胞。目的二:构建人源化气道上皮细胞,并对其进行鉴定。
hNSGF-SGM 3-IL 6-TSLP-TSLPR小鼠。我们将研究人类气道上皮细胞的发育,
将人支气管上皮祖细胞移植到NSGF-SGM 3-IL 6-TSLP-TSLPR小鼠(人源化或
不使用来自同一供体的HPC)通过人特异性靶的组织免疫荧光染色,
HLA I类。为了建立人气道上皮细胞的功能,我们将用活的
流感病毒和测量包括IL-33的物种特异性警报素的诱导; I型干扰素特征
作为其体内功能以及组织组成和吸引力的量度
人体免疫细胞与人体气道上皮细胞的结合。我们的假设是一个完整的TSLP信号通路
并且人上皮细胞将通过促进串扰来改善人源化小鼠中的人粘膜免疫
间质细胞和免疫细胞之间的联系。这个模型可以用于i。粘膜疫苗开发,以及
二.其他呼吸道病毒的研究,包括SARS-CoV-2,它需要人类特异性受体,
建立感染。因此,一旦获得认证,我们的模型将为未来的机制研究奠定基础,
在遗传可变供体的背景下体内粘膜免疫以及使粘膜免疫的研究成为可能。
佐剂、过敏原、疫苗和生物制剂。
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)
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Anna Karolina Palucka其他文献
Anna Karolina Palucka的其他文献
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{{ truncateString('Anna Karolina Palucka', 18)}}的其他基金
Modulation of Lung Immune Responses to Viral Infection
调节肺部对病毒感染的免疫反应
- 批准号:
10413443 - 财政年份:2021
- 资助金额:
$ 29.16万 - 项目类别:
Modulation of Viral Antigen Presentation in the Lung
肺部病毒抗原呈递的调节
- 批准号:
10436633 - 财政年份:2021
- 资助金额:
$ 29.16万 - 项目类别:
Modulation of Viral Antigen Presentation in the Lung
肺部病毒抗原呈递的调节
- 批准号:
10370726 - 财政年份:2020
- 资助金额:
$ 29.16万 - 项目类别:
Modulation of Lung Immune Responses to Viral Infection
调节肺部对病毒感染的免疫反应
- 批准号:
10265638 - 财政年份:2020
- 资助金额:
$ 29.16万 - 项目类别:
Modulation of Viral Antigen Presentation in the Lung
肺部病毒抗原呈递的调节
- 批准号:
10618415 - 财政年份:2020
- 资助金额:
$ 29.16万 - 项目类别:
Modulation of Lung Immune Responses to Viral Infection
调节肺部对病毒感染的免疫反应
- 批准号:
10399136 - 财政年份:2020
- 资助金额:
$ 29.16万 - 项目类别:
Modulation of Lung Immune Responses to Viral Infection
调节肺部对病毒感染的免疫反应
- 批准号:
10579861 - 财政年份:2019
- 资助金额:
$ 29.16万 - 项目类别:
Modulation of Viral Antigen Presentation in the Lung
肺部病毒抗原呈递的调节
- 批准号:
10113525 - 财政年份:2019
- 资助金额:
$ 29.16万 - 项目类别:
Modulation of Lung Immune Responses to Viral Infection
调节肺部对病毒感染的免疫反应
- 批准号:
10113511 - 财政年份:2019
- 资助金额:
$ 29.16万 - 项目类别:
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