Role of the thymic epithelium on the outcome of allogeneic transplantation
胸腺上皮对同种异体移植结果的作用
基本信息
- 批准号:8501268
- 负责人:
- 金额:$ 39.66万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-08-01 至 2015-07-31
- 项目状态:已结题
- 来源:
- 关键词:Allogeneic Bone Marrow TransplantationAllogenicAnimal ModelAnimalsAutoantigensAutoimmune ProcessAutoimmunityBiochemicalBiological PreservationBloodCell MaturationCellsCellular ImmunityCellularityClinicalDevelopmentDiseaseEpithelialEpithelial CellsEpitheliumGenerationsGenetically Modified AnimalsHematopoietic Stem Cell TransplantationHomologous TransplantationImmune responseImmune systemIndividualInjection of therapeutic agentInjuryLeadLigandsMalignant NeoplasmsMediatingMitogensMolecularMusNatural regenerationOutcomePeripheralPhysiologicalPopulationPreventionProcessRadiationReagentRecoveryRegimenRoleSignal TransductionSignaling ProteinSurfaceSymptomsT cell responseT-Cell Antigen Receptor SpecificityT-LymphocyteTestingTherapeutic AgentsTherapeutic InterventionThymic epithelial cellThymus GlandToxic effectToxicity due to chemotherapyTransplant RecipientsTransplantationTransplantation Conditioningagedautoreactive T cellbasecell mediated immune responsecellular targetingconditioningfibroblast growth factor 10graft vs host diseasegraft vs leukemia effectin vivoinsightkeratinocyte growth factorkeratinocyte growth factor receptorleukemiamouse modelnovelnovel strategiesnovel therapeuticspre-clinicalpreventprotective effectreceptorreconstitutionresearch studyresponserestorationsuccesstherapeutic targetthymocyte
项目摘要
DESCRIPTION (provided by applicant): The successful outcome of allogeneic hematopoietic stem-cell transplantation (HSCT) depends on the complete reconstitution of the host's immune system by donor-derived T cells. While an intact thymus is critically important for T cell reconstitution, thymus-dependent T cell repertoire restoration may be limited by changes in the thymic epithelium, brought about by transplant-mediated toxicities from chemotherapy/radiation regimens or graft vs. host disease (GVHD). The aim of this proposal is to examine whether boosting the thymic epithelium by in vivo administration of epithelial-cell-trophic-factors, exerts beneficial effects on T cell regeneration and prevention of GVHD following allogeneic bone marrow transplantation (allo-BMT). The trophic factors we will use in these experiments include keratinocyte growth factor (KGF) and receptor activator of NF?B ligand (RANKL) in conjunction to a genetically modified animal model deficient in expression of the signaling protein Sin. KGF is a potent epithelial cell mitogen which has been shown to expand the cortical and medullary thymic epithelium, increase thymopoiesis, and prevent the development of GVHD in preclinical mouse models. RANKL on the other hand, is important for development and differentiation of a subpopulation of medullary thymic epithelial cells (mTECs) involved in suppressing autoimmunity through elimination of autoreactive T cell clones. We recently found that Sin is expressed in the thymic epithelium and Sin deficiency inhibits KGF- and RANKL-induced expansion of thymic epithelial cells. In this proposal we will test the following hypothesis: KGF- and RANKL-mediated expansion of the thymic epithelium leads to better T cell reconstitution and protection from GVHD following allo-BMT. Sin deficiency inhibits KGF/RANKL signaling and ameliorates the beneficial effects of these factors after transplantation. To test this hypothesis we will: 1) Use allo-BMT mouse models in the Sin-deficient background to examine whether Sin is required for KGF-mediated a) T cell repertoire regeneration; b) reconstitution of T cell-mediated immune responses and c) protection from GVHD. 2) Examine whether RANKL administration can also protect from allo-BMT-related toxicity, whether it acts independently of or in conjunction with KGF and if Sin is required for the effects of RANKL in allo-BMT. 3) Use Sin deficient mice to identify the thymic epithelial cell targets of KGF and RANKL as well as elucidate the molecular mechanisms through which Sin regulates KGF/RANKL-mediated thymic epithelial cell expansion. We anticipate that these experiments will provide novel insight into how the thymic epithelium regulates thymopoiesis under normal or transplantation conditions, may identify RANKL and Sin as regulators of thymic epithelia-mediated T cell reconstitution following allo-BMT, and may lead to the identification of novel strategies/targets to better manage the outcome of HSCT.
描述(由申请人提供):同种异体造血干细胞移植(HSCT)的成功结果取决于供体来源的T细胞对宿主免疫系统的完全重建。虽然完整的胸腺对T细胞重建至关重要,但胸腺依赖性T细胞库的恢复可能受到胸腺上皮变化的限制,这些变化是由化疗/放疗方案或移植物抗宿主病(GVHD)引起的移植介导的毒性引起的。本研究的目的是研究体内给予上皮细胞营养因子是否对同种异体骨髓移植(alloc - bmt)后的T细胞再生和GVHD的预防有有益的影响。我们将在这些实验中使用的营养因子包括角化细胞生长因子(KGF)和NF受体激活因子?B配体(RANKL)与缺乏信号蛋白Sin表达的转基因动物模型相结合。KGF是一种有效的上皮细胞有丝分裂原,在临床前小鼠模型中已被证明可以扩大胸腺皮质和髓质上皮,增加胸腺增生,并阻止GVHD的发展。另一方面,RANKL对于胸腺髓质上皮细胞(mTECs)亚群的发育和分化很重要,这些细胞通过消除自身反应性T细胞克隆来抑制自身免疫。我们最近发现Sin在胸腺上皮中表达,并且Sin缺乏抑制KGF-和rankl诱导的胸腺上皮细胞的扩增。在本提案中,我们将验证以下假设:KGF和rankl介导的胸腺上皮扩张导致allo-BMT后更好的T细胞重建和对GVHD的保护。Sin缺乏抑制KGF/RANKL信号传导,并在移植后改善这些因素的有益作用。为了验证这一假设,我们将:1)使用在Sin缺失背景下的alloo - bmt小鼠模型来检查kgf介导的a) T细胞库再生是否需要Sin;b)重建T细胞介导的免疫反应和c)对GVHD的保护。2)研究RANKL是否也能保护机体免受同种异体bmt相关的毒性,它是否独立于KGF或与KGF联合作用,以及RANKL在同种异体bmt中的作用是否需要Sin。3)利用Sin缺陷小鼠,鉴定KGF和RANKL的胸腺上皮细胞靶点,阐明Sin调控KGF/RANKL介导的胸腺上皮细胞扩增的分子机制。我们预计这些实验将为在正常或移植条件下胸腺上皮如何调节胸腺生成提供新的见解,可能确定RANKL和Sin作为同种异体骨髓移植后胸腺上皮介导的T细胞重构的调节因子,并可能导致识别新的策略/靶点,以更好地管理HSCT的结果。
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 }}
KONSTANTINA ALEXANDROPOULOS其他文献
KONSTANTINA ALEXANDROPOULOS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('KONSTANTINA ALEXANDROPOULOS', 18)}}的其他基金
Microbiota-mediated T cell tolerance in newborn and adult autoimmunity-prone mice
新生和成年自身免疫小鼠中微生物群介导的 T 细胞耐受
- 批准号:
10463592 - 财政年份:2019
- 资助金额:
$ 39.66万 - 项目类别:
Microbiota-mediated T cell tolerance in newborn and adult autoimmunity-prone mice
新生和成年自身免疫小鼠中微生物群介导的 T 细胞耐受
- 批准号:
10229524 - 财政年份:2019
- 资助金额:
$ 39.66万 - 项目类别:
Microbiota-mediated T cell tolerance in newborn and adult autoimmunity-prone mice
新生和成年自身免疫小鼠中微生物群介导的 T 细胞耐受
- 批准号:
10020918 - 财政年份:2019
- 资助金额:
$ 39.66万 - 项目类别:
Microbiota-mediated T cell tolerance in newborn and adult autoimmunity-prone mice
新生和成年自身免疫小鼠中微生物群介导的 T 细胞耐受
- 批准号:
10684667 - 财政年份:2019
- 资助金额:
$ 39.66万 - 项目类别:
Mechanism of autoimmune hepatitis development in a novel mouse model
新型小鼠模型中自身免疫性肝炎发生的机制
- 批准号:
9516717 - 财政年份:2016
- 资助金额:
$ 39.66万 - 项目类别:
Role of the thymic epithelium on the outcome of allogeneic transplantation
胸腺上皮对同种异体移植结果的作用
- 批准号:
8308335 - 财政年份:2011
- 资助金额:
$ 39.66万 - 项目类别:
Role of the thymic epithelium on the outcome of allogeneic transplantation
胸腺上皮对同种异体移植结果的作用
- 批准号:
8107902 - 财政年份:2011
- 资助金额:
$ 39.66万 - 项目类别:
Role of Chat-H in chemokine-induced T lymphocyte migration and trafficking
Chat-H 在趋化因子诱导的 T 淋巴细胞迁移和运输中的作用
- 批准号:
7317277 - 财政年份:2007
- 资助金额:
$ 39.66万 - 项目类别:
Role of Chat-H in chemokine-induced T lymphocyte migration and trafficking
Chat-H 在趋化因子诱导的 T 淋巴细胞迁移和运输中的作用
- 批准号:
7802902 - 财政年份:2007
- 资助金额:
$ 39.66万 - 项目类别:
Role of Chat-H in chemokine-induced T lymphocyte migration and trafficking
Chat-H 在趋化因子诱导的 T 淋巴细胞迁移和运输中的作用
- 批准号:
8076331 - 财政年份:2007
- 资助金额:
$ 39.66万 - 项目类别:
相似海外基金
HLA-homozygous iPSC-cardiomyocytE Aggregate manufacturing technoLogies for allogenic cell therapy to the heart (HEAL)
HLA-纯合 iPSC-心肌细胞 用于心脏同种异体细胞治疗 (HEAL) 的聚集体制造技术
- 批准号:
10039902 - 财政年份:2022
- 资助金额:
$ 39.66万 - 项目类别:
EU-Funded
Evaluation of the efficacy of LAT1 inhibitor to tumor stroma and immunity in an allogenic mouse model of colon cancer having abundant stroma.
在具有丰富基质的同种异体结肠癌小鼠模型中评估 LAT1 抑制剂对肿瘤基质和免疫的功效。
- 批准号:
21K15925 - 财政年份:2021
- 资助金额:
$ 39.66万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Mechanism of kidney injury associated with graft-versus-host disease after allogenic stem cell transplantation
同种异体干细胞移植后移植物抗宿主病相关肾损伤的机制
- 批准号:
21K08410 - 财政年份:2021
- 资助金额:
$ 39.66万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Clarification of the origin and maintenance mechanisms of junctional epithelium and identification of its stem cells using allogenic tooth germ transplantation
阐明交界上皮的起源和维持机制并利用同种异体牙胚移植鉴定其干细胞
- 批准号:
20K21672 - 财政年份:2020
- 资助金额:
$ 39.66万 - 项目类别:
Grant-in-Aid for Challenging Research (Exploratory)
The study about the allogenic MSCs transplantation to the cardiac disease models.
同种异体间充质干细胞移植至心脏病模型的研究。
- 批准号:
18K16395 - 财政年份:2018
- 资助金额:
$ 39.66万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Artificial nerves containing allogenic basal lamellae scaffold and bone marrow derived stem cells
含有同种异体基底板层支架和骨髓干细胞的人工神经
- 批准号:
17K10951 - 财政年份:2017
- 资助金额:
$ 39.66万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Role of HSP90-alpha in preserving immunoprivilege of allogenic mesenchymal stem cells in the ischemic heart
HSP90-α 在保护缺血心脏同种异体间充质干细胞免疫特权中的作用
- 批准号:
370541 - 财政年份:2017
- 资助金额:
$ 39.66万 - 项目类别:
Operating Grants
Attempt to Prefabricate Vascularized Allogenic Bone in Recipient -Use of Cultured Bone Marrow Cells-
尝试在受者体内预制血管化的同种异体骨 - 使用培养的骨髓细胞 -
- 批准号:
16K10863 - 财政年份:2016
- 资助金额:
$ 39.66万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Allogenic micobiota-reconstitution (AMR) for the treatment of patients with diarhea-predominant irritable bowel syndrome (IBS-D) - the AMIRA trial
同种异体微生物群重建 (AMR) 用于治疗腹泻型肠易激综合征 (IBS-D) 患者 - AMIRA 试验
- 批准号:
276706135 - 财政年份:2015
- 资助金额:
$ 39.66万 - 项目类别:
Clinical Trials
Induction of thyme epithelial cells from iPS cells and application to allogenic transplantation
iPS细胞诱导百里香上皮细胞及其在同种异体移植中的应用
- 批准号:
15H04915 - 财政年份:2015
- 资助金额:
$ 39.66万 - 项目类别:
Grant-in-Aid for Scientific Research (B)