Depletion, Repopulation and Tolerance in Non-Sensitied Recipients

非敏感受体的消耗、再生和耐受性

基本信息

  • 批准号:
    10214495
  • 负责人:
  • 金额:
    $ 85.48万
  • 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:
    2017-08-15 至 2022-07-31
  • 项目状态:
    已结题

项目摘要

ABSTRACT – Project 1 (Kirk, Project Lead) Kidney transplantation's considerable benefit is offset by the many complications associated with chronic immunosuppressive therapy. Calcineurin inhibitor (CNI)-based regimens are used by over 95% of patients, but these indiscriminately impair immune processes, including those that facilitate graft acceptance, and produce significant side effects. Costimulation blockade (CoB), particularly CD28-CD80/86 pathway inhibition, has been shown to promote long-term allograft survival with fewer side effects than CNIs, and recent clinical trials have suggested that lymphocyte depletion fosters CoB-based regimens, not only preventing rejection, but fostering adaptive processes that reduce the needs for immunosuppression with time, and promoting allospecific tolerance. This project seeks to define the elements of lymphocyte depletion that foster CoB-based tolerance. We have shown that lymphocyte depletion, and subsequent homeostatic repopulation, present opportunities to shape the alloreactive immune repertoire to favor tolerance, but also poses risks to disrupt regulation, and ignite viral infection, autoimmunity and activation of alloreactive clones. Our experimental plan seeks to understand these two sides of depletional induction. We hypothesize that the effectiveness of therapeutic lymphocyte depletion is NOT driven by direct elimination of CoB-resistant cells, but rather by creating a stimulus for lymphocyte turnover and thymic output, fostering antigen-specific activation induced cell death (AICD). Viewed this way, the approach to depletion changes from cell elimination, to promoting and managing repopulation, the latter controlled by relative (not absolute), maturation-defined susceptibilities of the residual lymphocyte population to the effects of antigen exposure, secondary lymphoid organ function, and immunosuppression. We posit that these factors are tractable, and can be therapeutically manipulated. To explore this, we propose 3 specific aims: Specific Aim 1: We will define the effects of depletional induction regimens (broad polyclonal or targeted monoclonal antibody mediated depletion) in rhesus monkeys undergoing kidney transplantation, comparing the effects of CNIs and mTOR inhibitors on homeostatic repopulation, and relate these to the efficacy of belatacept-induced tolerance. Specific Aim 2: We will define the impact of thymic or splenic resection or irradiation on homeostatic repopulation of allospecific cells. Specific Aim 3: We will define the impact of donor and viral (CMV) antigen exposure on repopulation and tolerance, providing prolonged donor antigen in the form of bone marrow or mesenchymal stem cells, and studying these regimens in CMV naïve animals, animals with thymic irradiation. All studies will be heavily mechanistically supported to assess the phenotype, specificity and function of the repopulating repertoire. We will partner with Project 2 to define the impact of these maneuvers on alloantibody formation, and matrix the results in the Project with those of Project 2 to establish a paradigm to guide the development of an optimized depletional regimen to pair with CoB.
摘要-项目1 (Kirk,项目负责人)

项目成果

期刊论文数量(0)
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会议论文数量(0)
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Allan D. Kirk其他文献

Anti-IL12/23 synergizes with costimulatory blockade to prolong transplant survival
  • DOI:
    10.1016/j.jamcollsurg.2011.06.162
  • 发表时间:
    2011-09-01
  • 期刊:
  • 影响因子:
  • 作者:
    William H. Kitchens;Andrew B. Adams;Allan D. Kirk;Christian P. Larsen;Mandy L. Ford
  • 通讯作者:
    Mandy L. Ford
Necrosis and immune activation: does tissue death alter acquired alloimmunity?
  • DOI:
    10.1016/j.jamcollsurg.2013.07.331
  • 发表时间:
    2013-09-01
  • 期刊:
  • 影响因子:
  • 作者:
    Salila S. Hashmi;Mandy L. Ford;Christian P. Larsen;Allan D. Kirk
  • 通讯作者:
    Allan D. Kirk
B cells and transplantation tolerance
B 细胞与移植耐受
  • DOI:
    10.1038/nrneph.2010.111
  • 发表时间:
    2010-08-24
  • 期刊:
  • 影响因子:
    39.800
  • 作者:
    Allan D. Kirk;Nicole A. Turgeon;Neal N. Iwakoshi
  • 通讯作者:
    Neal N. Iwakoshi
Assessing Quality of Real-World Data Supplied by an Automated Surgical Data Pipeline
  • DOI:
    10.1016/j.jamcollsurg.2019.08.203
  • 发表时间:
    2019-10-01
  • 期刊:
  • 影响因子:
  • 作者:
    Kristin Corey;Joshua Helmkamp;Allan D. Kirk;Suresh Balu;David Thompson;Leila Mureebe;Joshua Watson;Keith Marsolo;Lesley Curtis;Mark Sendak
  • 通讯作者:
    Mark Sendak
Toll-Like Receptor Signaling as a Prognostic Tool in Trauma Patients
  • DOI:
    10.1016/j.jamcollsurg.2016.06.346
  • 发表时间:
    2016-10-01
  • 期刊:
  • 影响因子:
  • 作者:
    Marcus D. Darrabie;Jaewoo Lee;Jennifer Cheeseman;Alexander T. Limkakeng;Steven N. Vaslef;Bruce A. Sullenger;Allan D. Kirk
  • 通讯作者:
    Allan D. Kirk

Allan D. Kirk的其他文献

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{{ truncateString('Allan D. Kirk', 18)}}的其他基金

Advanced Immunobiology Traning Program for Surgeons
外科医生高级免疫生物学培训计划
  • 批准号:
    10598547
  • 财政年份:
    2019
  • 资助金额:
    $ 85.48万
  • 项目类别:
Advanced Immunobiology Traning Program for Surgeons
外科医生高级免疫生物学培训计划
  • 批准号:
    10396460
  • 财政年份:
    2019
  • 资助金额:
    $ 85.48万
  • 项目类别:
Depletion, Repopulation and Tolerance in Non-Sensitied Recipients
非敏感受体的消耗、再生和耐受性
  • 批准号:
    9980790
  • 财政年份:
    2017
  • 资助金额:
    $ 85.48万
  • 项目类别:
Computational Immunobiology Core
计算免疫生物学核心
  • 批准号:
    10622057
  • 财政年份:
    2017
  • 资助金额:
    $ 85.48万
  • 项目类别:
Depletion, Repopulation and Tolerance in Non-Sensitied Recipients
非敏感受体的消耗、再生和耐受性
  • 批准号:
    10649945
  • 财政年份:
    2017
  • 资助金额:
    $ 85.48万
  • 项目类别:
Cell Adhesion and Trafficking as a Therapeutic Target in Allotransplantation
细胞粘附和运输作为同种异体移植的治疗靶点
  • 批准号:
    8705985
  • 财政年份:
    2014
  • 资助金额:
    $ 85.48万
  • 项目类别:
T Cell Maturation and the Nexus of Viral- and Allo-Immunity
T 细胞成熟以及病毒免疫和同种异体免疫的关系
  • 批准号:
    8371823
  • 财政年份:
    2012
  • 资助金额:
    $ 85.48万
  • 项目类别:
T Cell Maturation and the Nexus of Viral- and Allo-Immunity
T 细胞成熟以及病毒免疫和同种异体免疫的关系
  • 批准号:
    8463978
  • 财政年份:
    2012
  • 资助金额:
    $ 85.48万
  • 项目类别:
T Cell Maturation and the Nexus of Viral- and Allo-Immunity
T 细胞成熟以及病毒免疫和同种异体免疫的关系
  • 批准号:
    8607811
  • 财政年份:
    2012
  • 资助金额:
    $ 85.48万
  • 项目类别:
ADJUVANT THERAPIES IMPROVING ANTI-REJECTION EFFECTS OF COSTIMULATION BLOCKADE
辅助疗法改善共同刺激封锁的抗排斥效果
  • 批准号:
    8357527
  • 财政年份:
    2011
  • 资助金额:
    $ 85.48万
  • 项目类别:

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