T cell fate decisions and transplant outcomes
T 细胞命运决定和移植结果
基本信息
- 批准号:10318164
- 负责人:
- 金额:$ 40.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-01-10 至 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAllograft ToleranceAllograftingApoptosisAreaAutoimmune DiseasesBiological AssayBone Marrow TransplantationCellsCessation of lifeChIP-seqChromatinChronicClinicClinicalCoupledDevelopmentDiseaseEnhancersEnsureEpigenetic ProcessExperimental ModelsFOXP3 geneGoalsGraft SurvivalGraft ToleranceHeart TransplantationHelper-Inducer T-LymphocyteHomebound PersonsImmuneImmunityImmunocompromised HostImmunosuppressionInflammationInflammatoryInterleukin-4Interleukin-9Knockout MiceKnowledgeLifeMediatingModelingMolecular GeneticsMusOX40Organ TransplantationOutcomePatientsPharmaceutical PreparationsPharmacologyProceduresProtocols documentationRegulatory T-LymphocyteReporterResistanceRoleSavingsSignal TransductionStructureT-LymphocyteTestingTh2 CellsTherapeutic immunosuppressionTissuesToxic effectTransforming Growth Factor betaTransplant RecipientsTransplantationWood materialbasecancer immunotherapycofactorconditional knockoutcostcytokinedesigneffector T cellfundamental researchgenetic approachimprovedinhibitorinsightmemory CD4 T lymphocytenovelnovel therapeuticsprogramsresponsetheoriestherapeutic targettooltranscription factortransplant modeltransplantation therapy
项目摘要
Project Summary
Rejection remains a major hurdle to long-lasting transplant survival. From a clinical standpoint current
immunosuppression protocols are fantastic in short-term transplant survival, but do little in promoting long-
term graft outcomes. Thus, there is a pressing need to uncover effector programs that may emerge under
broad immunosuppressive conditions that can mediate graft loss, with a goal of further improving long term
transplant outcomes. We recently discovered that unlike other Th subsets, Th9 cells are robustly induced in
an immunosuppressive milieu, suggesting that Th9 cells may be especially relevant to graft loss under
conditions of immunosuppression. Th9 cells are induced in massive numbers when the default Th1/Th2
programs are inhibited and require the formation of super-enhancers at Il9 locus (not lineage specific
transcription factors). Importantly, formation of Il9 super-enhancers requires OX40 signaling. Also, OX40 is
remarkably potent in redirecting Foxp3+ Tregs to inflammatory Th9 cells. Based on the unexpected potency
of OX40 in robust Th9 induction, as well as the unexpected mode of actions of OX40 stimulation, we
propose to test a unifying hypothesis in this proposal, namely- suppression of the default T cell programs in
an immunosuppressive milieu allows OX40 to promote alternative Th9 programs in triggering rejection of
otherwise tolerant grafts. We propose 3 Aims in this proposal. Aim 1 focuses on identifying novel
mechanisms by which OX40 promotes massive Th9 cells, examining formation, structure, and activities of
super-enhancers at Il9 locus. Aim 2 investigates how OX40 redirects Foxp3+ Tregs to Th9 cells, focusing
on the newly identified Foxp3 repressors in shutting down Foxp3 expression and examine whether Foxp3
may disrupt IL-9 super enhancer formations. Aim 3 examines the impact of Th9 cells in transplant survival,
testing whether targeting super-enhancers or checkpoints in Th9 induction enables robust allograft
tolerance. We believe that the proposed studies will unravel new mechanisms of tolerance resistance in
transplant recipients, and findings from these studies will have broad impacts on other immune-mediated
diseases as well, including cancer immunotherapies and autoimmune diseases.
项目摘要
排斥反应仍然是移植长期生存的主要障碍。从临床角度来看,
免疫抑制方案在短期移植存活率方面非常好,但在促进长期移植存活方面却收效甚微。
长期移植结果。因此,迫切需要揭示可能出现的效应程序,
广泛的免疫抑制条件,可以介导移植物丢失,目标是进一步改善长期
移植结果我们最近发现,与其他Th亚群不同,Th 9细胞在体内被强烈诱导,
免疫抑制环境,表明Th 9细胞可能与移植物丢失特别相关,
免疫抑制的条件。当默认的Th 1/Th 2/Th 3/Th 4/Th 6/Th 7/Th 8/Th 9/Th
程序被抑制并且需要在Il 9基因座处形成超级增强子(非谱系特异性
转录因子)。重要的是,Il 9超级增强子的形成需要0X 40信号传导。OX 40是
在将Foxp 3 + T细胞重定向至炎性Th 9细胞方面具有显著效力。基于这种意想不到的效力
在稳健的Th 9诱导中的OX 40,以及OX 40刺激的意外作用模式,我们
我建议在这个建议中测试一个统一的假设,即-抑制默认的T细胞程序,
免疫抑制环境允许OX 40促进替代性Th 9程序,触发免疫排斥,
其他耐受性移植物。我们在这个建议中提出了三个目标。目标1侧重于识别新的
OX 40促进大量Th 9细胞的机制,研究了OX 40的形成,结构和活性。
Il 9基因座处的超级增强子。目的2研究了OX 40如何将Foxp 3 + T细胞重定向至Th 9细胞,
新鉴定的Foxp 3阻遏物在关闭Foxp 3表达中的作用,并检查Foxp 3
可能破坏IL-9超级增强子的形成。目的3检查Th 9细胞在移植存活中的影响,
测试在Th 9诱导中靶向超级增强子或检查点是否能够实现稳健的同种异体移植
宽容我们相信,拟议的研究将揭示新的耐药机制,
这些研究的结果将对其他免疫介导的疾病产生广泛的影响。
疾病,包括癌症免疫疗法和自身免疫性疾病。
项目成果
期刊论文数量(11)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
OX40 Costimulation Inhibits Foxp3 Expression and Treg Induction via BATF3-Dependent and Independent Mechanisms.
- DOI:10.1016/j.celrep.2018.06.052
- 发表时间:2018-07-17
- 期刊:
- 影响因子:8.8
- 作者:Zhang X;Xiao X;Lan P;Li J;Dou Y;Chen W;Ishii N;Chen S;Xia B;Chen K;Taparowsky E;Li XC
- 通讯作者:Li XC
Ox40-Cre-mediated deletion of BRD4 reveals an unexpected phenotype of hair follicle stem cells in alopecia.
- DOI:10.1172/jci.insight.164534
- 发表时间:2022-12-08
- 期刊:
- 影响因子:8
- 作者:Wen, Mou;Ying, Yuanlin;Xiao, Xiang;Arnold, Preston R.;Wang, Guangchuan;Chu, Xiufeng;Ghobrial, Rafik M.;Li, Xian C.
- 通讯作者:Li, Xian C.
Genetically targeting the BATF family transcription factors BATF and BATF3 in the mouse abrogates effector T cell activities and enables long-term heart allograft survival.
- DOI:10.1111/ajt.16861
- 发表时间:2022-03
- 期刊:
- 影响因子:0
- 作者:Wang Y;Xiao X;Kong G;Wen M;Wang G;Ghobrial RM;Dong N;Chen W;Li XC
- 通讯作者:Li XC
Suppression of FOXP3 expression by the AP-1 family transcription factor BATF3 requires partnering with IRF4.
- DOI:10.3389/fimmu.2022.966364
- 发表时间:2022
- 期刊:
- 影响因子:7.3
- 作者:
- 通讯作者:
Guidance of super-enhancers in regulation of IL-9 induction and airway inflammation.
- DOI:10.1084/jem.20170928
- 发表时间:2018-02-05
- 期刊:
- 影响因子:0
- 作者:Xiao X;Fan Y;Li J;Zhang X;Lou X;Dou Y;Shi X;Lan P;Xiao Y;Minze L;Li XC
- 通讯作者:Li XC
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Xian Chang Li其他文献
An update on regulatory T cells in transplant tolerance and rejection
移植耐受与排斥中调节性 T 细胞的最新进展
- DOI:
10.1038/nrneph.2010.101 - 发表时间:
2010-08-03 - 期刊:
- 影响因子:39.800
- 作者:
Xian Chang Li;Laurence A. Turka - 通讯作者:
Laurence A. Turka
Vascularized Composite Allotransplantation Research: The Emerging Field
血管化复合同种异体移植研究:新兴领域
- DOI:
- 发表时间:
2012 - 期刊:
- 影响因子:8.8
- 作者:
Bohdan Pomahac;Yolanda T. Becker;L. Cendales;S. Ildstad;Xian Chang Li;S. Schneeberger;M. Siemionow;A. Thomson;Xin Xiao Zheng;Stefan G. Tullius - 通讯作者:
Stefan G. Tullius
IL-2 receptor-targeted cytolytic IL-2/Fc fusion protein treatment blocks diabetogenic autoimmunity in nonobese diabetic mice.
IL-2 受体靶向细胞溶解性 IL-2/Fc 融合蛋白治疗可阻断非肥胖糖尿病小鼠的糖尿病性自身免疫。
- DOI:
- 发表时间:
1999 - 期刊:
- 影响因子:4.4
- 作者:
X. Zheng;A. Steele;Wayne W. Hancock;Kensaku Kawamoto;Xian Chang Li;Peter W. Nickerson;Yongsheng Li;Yan Tian;Terry B. Strom - 通讯作者:
Terry B. Strom
Facile synthesis of rare earth ions doped LiSrsub4/sub(BNsub2/sub)sub3/sub phosphors for white light-emitting diodes
用于白光发光二极管的稀土离子掺杂的 LiSr₄(BN₂)₃ 荧光粉的简便合成
- DOI:
10.1016/j.jallcom.2024.175052 - 发表时间:
2024-09-15 - 期刊:
- 影响因子:6.300
- 作者:
Wenqin Luo;Yongya Wang;Xian Chang Li;Haiyan Wu - 通讯作者:
Haiyan Wu
Blood monocyte migration to acute lung inflammation involves both CD11/CD18 and very late activation antigen-4-dependent and independent pathways.
血液单核细胞向急性肺部炎症的迁移涉及 CD11/CD18 和非常晚期激活抗原 4 依赖性和独立途径。
- DOI:
- 发表时间:
1998 - 期刊:
- 影响因子:4.4
- 作者:
Xian Chang Li;Masayuki Miyasaka;T. Issekutz - 通讯作者:
T. Issekutz
Xian Chang Li的其他文献
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{{ truncateString('Xian Chang Li', 18)}}的其他基金
Modulation of innate immune cells to create transplant tolerance
调节先天免疫细胞以产生移植耐受
- 批准号:
8078381 - 财政年份:2011
- 资助金额:
$ 40.38万 - 项目类别:
Modulation of innate immune cells to create transplant tolerance
调节先天免疫细胞以产生移植耐受
- 批准号:
8232053 - 财政年份:2011
- 资助金额:
$ 40.38万 - 项目类别:
Modulation of innate immune cells to create transplant tolerance
调节先天免疫细胞以产生移植耐受
- 批准号:
8628733 - 财政年份:2011
- 资助金额:
$ 40.38万 - 项目类别:
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