Impact of Microbiota on Alloimmune Responses in Transplantation
移植中微生物群对同种免疫反应的影响
基本信息
- 批准号:10304904
- 负责人:
- 金额:$ 48.04万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-11-03 至 2024-11-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAllograftingAnimalsAntibioticsBacteriaBacteroides thetaiotaomicronCell physiologyClinicalCollectionDataDendritic CellsDistalEtiologyFecesFundingGeneticGerm-FreeGnotobioticGraft RejectionGraft SurvivalHalf-LifeHeartHeart TransplantationImmuneImmune responseImmune systemImmunosuppressionImmunosuppressive AgentsIndividualIndividual DifferencesInterferonsInterventionIntestinesKidney TransplantationKineticsLocationLungLung TransplantationMHC Class II GenesMicrobeMinorMusOrganOrgan DonorOrgan TransplantationOutcomePharmacologyPhaseProbioticsRoleSiteSkinSkin TransplantationSkin colonizationSkin graftSmall IntestinesStaphylococcus aureusStaphylococcus epidermidisSterilityStomachSystemT-LymphocyteTherapeuticTissue DonorsTissuesTransgenic OrganismsTransplantationallograft rejectionclinically relevantdraining lymph nodeexperimental studyfecal microbiomefecal microbiotagenetic signaturegerm free conditiongut colonizationgut microbiotaheart allografthost colonizationimprovedinsightisoimmunitymicrobialmicrobial communitymicrobiotamigrationnegative affectnovelprebioticsreconstitutionresponseside effectskin allograft
项目摘要
PROJECT SUMMARY
The strength of an immune response against a transplanted organ, termed the alloresponse, depends
on the extent of genetic differences between the donor and the recipient and their recognition by the recipient’s
immune system. Our studies from the previous funding cycle have shown that the microbiota, the collection of
microbes that colonize the body and differ between individuals, is an additional novel factor that can causally
modulate the intensity and kinetics of the alloresponse to a transplanted organ. Unlike donor and host genetics,
the microbiota can be manipulated therapeutically, thus providing possible new interventions to protect the graft
and help reduce the need for immunosuppressive drugs that can cause significant side effects.
We initially considered the body’s microbiota as a whole and demonstrated that a reduction in microbial
diversity induced by broad-spectrum antibiotic (Abx) pre-treatment, or an absence of microbiota using germ-free
(GF) mice, both improved minor mismatched skin graft survival. Fecal microbiome transfer (FMT) from control,
but not Abx-pre-treated mice, into GF mice was sufficient to accelerate skin graft rejection. This demonstrated
both the causality of the microbiota on affecting graft outcome, and the divergent effects of distinct fecal microbial
communities. Abx pre-treatment also delayed rejection of fully mismatched skin grafts, minor mismatched lung
grafts, and MHC class II-mismatched heart grafts, indicating that whole-body microbiota affects the outcome of
both colonized and sterile organs. We further showed that that some microbial communities could be dominantly
protective of rejection. This protection was associated with fecal presence of bacteria of the genus Alistipes.
In addition, the half-life of small bowel, lung and skin transplants is much shorter than that of heart and
kidney grafts, supporting the hypothesis that the commensals in the graft may also be able to influence
alloimmunity. Our recent preliminary experiments demonstrate that colonization of donor skin with the single
commensal Staphylococcus epidermidis (S. epi), in the absence of intestinal colonization of the host, can be
sufficient to accelerate skin graft rejection. This result clearly demonstrates that microbiota within the allograft
also impacts graft outcome. Notably, the mechanism by which skin S. epi accelerates skin graft rejection appears
different from how whole-body microbiota in SPF mice or FMT into GF mice accelerates skin graft rejection. We
hypothesize a novel paradigm that the recipient gut microbiota affects immune responses in the whole animal
by systemically modulating DCs up or down, whereas the microbiota in the donor graft locally affects the effector
phase of the alloresponse upon migration of recipient alloreative T cells into the graft. Using a combination of
TCR transgenic T cells and p:MHC multimers to track anti-commensal and anti-donor immune responses in
parallel, as well as select bacterial colonization of distinct tissues in gnotobiotic mice, we will: 1. Investigate the
mechanisms by which gut-only microbes can impact skin graft rejection distally; 2. Define the
mechanisms by which skin-only commensals locally accelerate skin graft rejection.
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)
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 }}
Maria-Luisa Alegre其他文献
Maria-Luisa Alegre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('Maria-Luisa Alegre', 18)}}的其他基金
Immunoengineering Postdoctoral Training Program - Resubmission - 1
免疫工程博士后培养计划-重新提交-1
- 批准号:
10471904 - 财政年份:2021
- 资助金额:
$ 48.04万 - 项目类别:
Immunoengineering Postdoctoral Training Program - Resubmission - 1
免疫工程博士后培养计划-重新提交-1
- 批准号:
10671538 - 财政年份:2021
- 资助金额:
$ 48.04万 - 项目类别:
Immunoengineering Postdoctoral Training Program - Resubmission - 1
免疫工程博士后培养计划-重新提交-1
- 批准号:
10270986 - 财政年份:2021
- 资助金额:
$ 48.04万 - 项目类别:
The microbiota and allograft rejection: novel investigations into the consequences of obesity
微生物群和同种异体移植排斥:对肥胖后果的新研究
- 批准号:
10204895 - 财政年份:2017
- 资助金额:
$ 48.04万 - 项目类别:
Impact of Microbiota on Alloimmune Responses in Transplantation
移植中微生物群对同种免疫反应的影响
- 批准号:
8824774 - 财政年份:2014
- 资助金额:
$ 48.04万 - 项目类别:
Impact of Microbiota on Alloimmune Responses in Transplantation
移植中微生物群对同种免疫反应的影响
- 批准号:
9905681 - 财政年份:2014
- 资助金额:
$ 48.04万 - 项目类别:
Impact of Microbiota on Alloimmune Responses in Transplantation
移植中微生物群对同种免疫反应的影响
- 批准号:
10528456 - 财政年份:2014
- 资助金额:
$ 48.04万 - 项目类别:
Impact of Microbiota on Alloimmune Responses in Transplantation
移植中微生物群对同种免疫反应的影响
- 批准号:
9170958 - 财政年份:2014
- 资助金额:
$ 48.04万 - 项目类别:
Infections and the Stability of Transplantation Tolerance
感染和移植耐受的稳定性
- 批准号:
10176362 - 财政年份:2012
- 资助金额:
$ 48.04万 - 项目类别:
相似海外基金
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 48.04万 - 项目类别:
Training Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 48.04万 - 项目类别:
Standard Grant
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 48.04万 - 项目类别:
Standard Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 48.04万 - 项目类别:
Fellowship
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 48.04万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 48.04万 - 项目类别:
Research Grant
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 48.04万 - 项目类别:
Studentship
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 48.04万 - 项目类别:
Operating Grants
New Tendencies of French Film Theory: Representation, Body, Affect
法国电影理论新动向:再现、身体、情感
- 批准号:
23K00129 - 财政年份:2023
- 资助金额:
$ 48.04万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
The Protruding Void: Mystical Affect in Samuel Beckett's Prose
突出的虚空:塞缪尔·贝克特散文中的神秘影响
- 批准号:
2883985 - 财政年份:2023
- 资助金额:
$ 48.04万 - 项目类别:
Studentship