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

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:
Administration and Biostatistics
行政管理和生物统计学
  • 批准号:
    10596902
  • 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:
Administration and Biostatistics
行政管理和生物统计学
  • 批准号:
    10217983
  • 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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ATTAC 时间:针对 gp100 细胞的 T 细胞过继转移来治疗 LAM
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