Regulatory immune cell therapy, promotion of tolerance and underlying mechanisms in NHP renal transplantation
NHP肾移植中的调节性免疫细胞治疗、耐受性促进及潜在机制
基本信息
- 批准号:10518430
- 负责人:
- 金额:$ 104.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-08-17 至 2024-04-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAdoptive TransferAffectAllograftingAnti-Inflammatory AgentsAwardBiopsyBiostatistics CoreCOVID-19 pandemicCalcineurinCell TherapyCell physiologyCellsCellular immunotherapyClinicalDendritic CellsDoseFc ReceptorFundingGraft SurvivalImmuneImmune ToleranceImmunosuppressive AgentsInflammationInfusion proceduresInterleukin 6 ReceptorInterleukin-2Kidney TransplantationLeadMacaca mulattaMaintenanceModelingModificationMononuclearNational Institute of Allergy and Infectious DiseaseOrgan TransplantationOutcomePeer ReviewPlayProtocols documentationReagentRegimenRegulatory T-LymphocyteResearchResourcesRhesusRoleSirolimusSite VisitTacrolimusTestingTherapeutic EffectTimeTissue imagingTransplantationTransplantation ToleranceTreatment EfficacyVaccinesWorkclinically relevantconditioningdesignexperimental studyimmunoregulationimprovedin vivokidney allograftlymph nodesnonhuman primatenovelnovel markerpandemic diseasepathology imagingperipheral bloodpost-transplantprogramsresponsesuccesssynergismtherapeutically effectivetransplantation therapy
项目摘要
Our objective in this U19 is to develop a safe and effective therapeutic approach to promote organ transplant
tolerance in a clinically-relevant, nonhuman primate model. Two promising complementary but interactive
approaches to adoptive immune cell therapy for transplant tolerance,- regulatory dendritic cells (DCreg) and
regulatory T cells (Treg) and their combination, comprise this U19 application. Work already completed during
the award shows that, using a minimal immunosuppressive (IS) drug regimen of tapering calcineurin inhibition
(tacrolimus) combined with co-stimulation blockade (CTLA4Ig), MHC-mismatched renal allograft graft
survival can be prolonged using either cell therapy alone. Thus, administration of donor-derived DCreg a
week before transplant, or delayed administration of Treg commencing 7 weeks post-transplant, prolongs
median kidney graft survival time in rhesus macaques, although transplant tolerance is not induced. As in
the original funded award, we hypothesize that, using the same immunosuppressive drug regimen,
incorporation of the combined immunomodulatory functions of adoptively-transferred DCreg before
transplant and Treg post-transplant will promote IS drug-free, donor-specific tolerance. In this type-4
Extension, we will complete mechanistic studies (delayed as the result of institutional restrictions imposed
in response to the COVID-19 pandemic) designed to improve understanding of the in vivo fate of each cell
product and how each cell therapy affects anti-donor immune reactivity, with emphasis on their impact on
immune effector and regulatory cell functions. In addition, the Extension will allow us perform the delayed
combined cell therapy transplant experiments proposed in our funded award, in which we will (in Project 1)
test the combined DCreg + Treg approach and (in Project 2) the potential of the anti-inflammatory agent
anti-IL-6 receptor antibody to potentiate the therapeutic effect of the combined cell therapy regimen. In both
projects, mechanistic studies will be performed on peripheral blood and lymph node mononuclear cells and
graft biopsies to elucidate underlying mechanisms. The proposed studies will take advantage of the success
we have achieved during the U19 award in expanding highly-suppressive, donor-alloreactive rhesus Treg
(arTreg) ex vivo. The Aims of the two Projects for the Extension are:
Project 1
Aim 1: To complete mechanistic studies concerning the influence of pre-or post-transplant infusion
of donor-derived DCreg on rhesus renal allograft survival
Aim 2: To perform combined pre-transplant DCreg infusion with delayed post-transplant arTreg
infusion on rhesus renal allograft survival and accompanying mechanistic studies
Project 2
Aim 1: To complete mechanistic studies concerning the impact of IL-6R blockade on kidney graft
survival and the therapeutic efficacy of ex vivo-expanded arTreg
Aim 2: To determine the impact of IL-6R blockade on kidney allograft survival in conjunction with
combined cell therapy and underlying mechanisms
In addition to highly-interactive, mechanistic studies, both Projects will assess novel biomarker
(eomesodermin) expression by alloreactive Tmem as a potential predictor of transplant outcome/tolerance.
The Projects will be supported by the Administrative and Biostatistics Core (Core A) and the Transplant
Pathology and Tissue Imaging Core (Core B) and will utilize agents from the NIAID NHP Reagent
Resource.
我们的目标是开发一种安全有效的治疗方法来促进器官移植
项目成果
期刊论文数量(3)
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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Angus W Thomson其他文献
Transplant Tolerance Induction: Insights From the Liver
- DOI:
- 发表时间:
2020 - 期刊:
- 影响因子:
- 作者:
Helong Dai;Yawen Zheng;Angus W Thomson;Natasha M Rogers - 通讯作者:
Natasha M Rogers
Organ transplantation—how much of the promise has been realized?
器官移植——兑现了多少承诺?
- DOI:
10.1038/nm1251 - 发表时间:
2005-06-03 - 期刊:
- 影响因子:50.000
- 作者:
Robert I Lechler;Megan Sykes;Angus W Thomson;Laurence A Turka - 通讯作者:
Laurence A Turka
Angus W Thomson的其他文献
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{{ truncateString('Angus W Thomson', 18)}}的其他基金
Regulatory Dendritic Cell Therapy in Live Donor Renal Transplant Recipients
活体肾移植受者的调节性树突状细胞治疗
- 批准号:
9924470 - 财政年份:2018
- 资助金额:
$ 104.13万 - 项目类别:
Regulatory Dendritic Cell Therapy in Live Donor Renal Transplant Recipients
活体肾移植受者的调节性树突状细胞治疗
- 批准号:
10153679 - 财政年份:2018
- 资助金额:
$ 104.13万 - 项目类别:
Regulatory Dendritic Cell Therapy in Live Donor Renal Transplant Recipients
活体肾移植受者的调节性树突状细胞治疗
- 批准号:
10396484 - 财政年份:2018
- 资助金额:
$ 104.13万 - 项目类别:
Regulation of Liver DC Function and Transplant Tolerance
肝脏 DC 功能和移植耐受的调节
- 批准号:
9927591 - 财政年份:2017
- 资助金额:
$ 104.13万 - 项目类别:
Regulatory immune cell therapy, promotion of tolerance and underlying mechanisms in NHP renal transplantation
NHP肾移植中的调节性免疫细胞治疗、耐受性促进及潜在机制
- 批准号:
9329522 - 财政年份:2017
- 资助金额:
$ 104.13万 - 项目类别:
Regulatory immune cell therapy, promotion of tolerance and underlying mechanisms in NHP renal transplantation
NHP肾移植中的调节性免疫细胞治疗、耐受性促进及潜在机制
- 批准号:
10217982 - 财政年份:2017
- 资助金额:
$ 104.13万 - 项目类别:
Regulatory dendritic cell therapy, promotion of tolerance and underlying mechanisms in NHP renal transplantation
NHP 肾移植中的调节性树突状细胞治疗、耐受性促进及潜在机制
- 批准号:
10596904 - 财政年份:2017
- 资助金额:
$ 104.13万 - 项目类别:
Regulation of Liver DC Function and Transplant Tolerance
肝脏 DC 功能和移植耐受的调节
- 批准号:
9372923 - 财政年份:2017
- 资助金额:
$ 104.13万 - 项目类别:
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