Immunological and functional consequences triggered by the gut microbiota regulate alloimmunity and cardiac transplant outcome
肠道微生物群引发的免疫和功能后果调节同种免疫和心脏移植结果
基本信息
- 批准号:9795098
- 负责人:
- 金额:$ 57.87万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-07-15 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:AcuteAdoptive Cell TransfersAffectAlloantigenAllogenicAllograftingAnti-inflammatoryAntibiotic TherapyAntibioticsAntigensAntiinflammatory EffectAutoantigensAutoimmune DiseasesB-LymphocytesBacteriaBifidobacteriumBiological AssayBloodBlood VesselsCardiacCell WallCellsChemical StructureChronicCicatrixClassificationComorbidityDendritic CellsDesulfovibrioDiagnosticDiseaseDistalDistantEndothelial CellsEpithelialEventFOXP3 geneFailureFibrosisFunctional disorderGeneticGoalsGraft SurvivalHeart TransplantationHistologyHomeostasisHumanImmuneImmune System DiseasesImmune systemImmunityImmunohistochemistryImmunologic MonitoringImmunologicsImmunologyImmunosuppressionImmunosuppressive AgentsIn VitroInfectionInflammationInflammatoryInnate Immune ResponseIntestinesInvestigationKidney TransplantationLamininLinkLymphaticLymphocyteLymphoid CellModelingMolecularMonitorMusMyelogenousMyeloid CellsNatural ImmunityNatureNucleic AcidsOrganOrgan DonorOrgan PreservationOrgan TransplantationOutcomePathologyPathway interactionsPharmacologyPhysiologicalPopulationProceduresPropertyProphylactic treatmentRegimenRegulatory T-LymphocyteReportingSignal TransductionSolidStructureSurvival RateT-LymphocyteTestingTherapeutic immunosuppressionTransplantationWorkadaptive immunityallograft rejectionbaseclinically relevantdiagnostic biomarkerdriving forceexperimental studygraft functiongraft vs host diseasegut microbiotaheart allografthost microbiotaimprovedin vivointerstitialisoimmunitylymph nodesmacrophagemicrobialmicrobiotamigrationmouse modelnovelnovel strategiesreceptorresponsesuccesstherapeutic targettooltraffickingtransplant modeltransplantation medicinevascular inflammation
项目摘要
Project Summary
Many aspects of the innate and adaptive immunity are critically regulated by the microbiota. Microbial
cells, their metabolites and nucleic acids engage various immune cells, resulting in pro- or anti-inflammatory
signals that differ based on chemical structures, cellular receptors, and physiological context. The microbiota
not only influences local immunity, but also has distant effects on systemic immunity. Local microbiota
stimulation of innate and adaptive immune cells results in those cells or their products to migrate or traffic
through lymphatics or blood, and influence diseases. However, the precise causal pathways linking microbiota
components to immune cells and downstream effectors in most cases remain to be defined.
Solid organ transplantation has made significant progress over the past 35 years and has become a
routine procedure. Cardiac transplantation is a common and successful transplant, with graft survival after one
year exceeding 80-90%. Despite advances in all aspects of allografting, the rate of decline of cardiac and other
graft function beyond the first year after transplant has not changed in over 20 years. All allografts eventually
succumb to chronic vascular, interstitial or epithelial changes. Despite critical improvements in
immunosuppressive regimens, immunologic monitoring, and molecular classification of organ pathology,
chronic rejection still persists and its primary cause is not understood. Prior work has focused on distal events
of fibrosis and inflammation, but not on proximal causes of inflammation and immunity.
We previously showed in renal transplantation, large and persistent shifts in the composition and
complexity of the gut microbiota as a result of immunosuppression and antibiotics. Such shifts in the microbiota
are indicative of all organ transplants, including cardiac transplants. We therefore hypothesized that these
changes could critically affect graft outcome. Our current studies dissected the interactions between the enteric
microbiota and innate and adaptive immunity, in clinically-relevant cardiac transplantation models of acute and
chronic rejection. Our results show that both pro-inflammatory and anti-inflammatory microbiota populations, as
well as single bacteria, can be defined by their effects on the long-term outcome of the grafts. Mechanistic
explorations suggest a differential stimulation of myeloid cells (i.e. macrophages and DC), resulting in changes
in LN structure that influence allogeneic immunity. Thus, we hypothesize that the microbiota directly regulates
innate immunity, which in turn regulates systemic inflammation and adaptive immunity, thereby determining the
occurrence and progression of graft fibrosis, inflammation and graft survival. To investigate this hypothesis, we
will take advantage of our expertise in microbiota analysis and in molecular and cellular transplant
immunology. The definition of pro-inflammatory and anti-inflammatory microbiota and strains may provide a
precise platform to define the most important upstream influences that initiate organ inflammation and scarring
and could serve as potent diagnostic markers for allograft management.
项目总结
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)
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Jonathan S Bromberg其他文献
Islet implantation in a pocket
胰岛植入在囊中
- DOI:
10.1038/nbt.3216 - 发表时间:
2015-05-12 - 期刊:
- 影响因子:41.700
- 作者:
Jonathan S Bromberg - 通讯作者:
Jonathan S Bromberg
Jonathan S Bromberg的其他文献
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{{ truncateString('Jonathan S Bromberg', 18)}}的其他基金
Mechanisms of microbiome-driven cardiac allograft outcomes
微生物组驱动的同种异体心脏移植结果的机制
- 批准号:
10477625 - 财政年份:2022
- 资助金额:
$ 57.87万 - 项目类别:
Mechanisms of microbiome-driven cardiac allograft outcomes
微生物组驱动的同种异体心脏移植结果的机制
- 批准号:
10621899 - 财政年份:2022
- 资助金额:
$ 57.87万 - 项目类别:
Reshaping lymph node stroma for transplant tolerance
重塑淋巴结基质以提高移植耐受性
- 批准号:
10662321 - 财政年份:2020
- 资助金额:
$ 57.87万 - 项目类别:
Reshaping lymph node stroma for transplant tolerance
重塑淋巴结基质以提高移植耐受性
- 批准号:
10224026 - 财政年份:2020
- 资助金额:
$ 57.87万 - 项目类别:
Reshaping lymph node stroma for transplant tolerance
重塑淋巴结基质以提高移植耐受性
- 批准号:
10024598 - 财政年份:2020
- 资助金额:
$ 57.87万 - 项目类别:
Reshaping lymph node stroma for transplant tolerance
重塑淋巴结基质以提高移植耐受性
- 批准号:
10431927 - 财政年份:2020
- 资助金额:
$ 57.87万 - 项目类别:
Immunological and functional consequences triggered by the gut microbiota regulate alloimmunity and cardiac transplant outcome
肠道微生物群引发的免疫和功能后果调节同种免疫和心脏移植结果
- 批准号:
10439697 - 财政年份:2019
- 资助金额:
$ 57.87万 - 项目类别:
Immunological and functional consequences triggered by the gut microbiota regulate alloimmunity and cardiac transplant outcome
肠道微生物群引发的免疫和功能后果调节同种免疫和心脏移植结果
- 批准号:
10202721 - 财政年份:2019
- 资助金额:
$ 57.87万 - 项目类别:
Immunological and functional consequences triggered by the gut microbiota regulate alloimmunity and cardiac transplant outcome
肠道微生物群引发的免疫和功能后果调节同种免疫和心脏移植结果
- 批准号:
9975884 - 财政年份:2019
- 资助金额:
$ 57.87万 - 项目类别:
U Maryland Mid-Atlantic APOLLO Research Network Omic and Clinical Center
马里兰大学大西洋中部阿波罗研究网络组学和临床中心
- 批准号:
10729890 - 财政年份:2017
- 资助金额:
$ 57.87万 - 项目类别: