Calcineurin Inhibitor Minimization And Foxp3+ Tregs Post-Transplant

描述(由调查人员提供)：费城儿童医院(CHOP)为当地经济做出了巨大贡献。2008年，CHOP的业务在该地区创造和支持了超过16,882个工作岗位，CHOP的总经济影响超过59亿美元。此外，通过私人捐款、NIH资助和医院运营拨款，CHOP获得的研究资助总额比美国其他任何一家儿童医院都多--2007-2008财年为1.8亿美元。当前申请将创造或保留6个工作岗位。我们希望通过优化当前的患者护理来改善移植受者的预后。实体器官移植的接受者长期面临感染、肾功能障碍、恶性肿瘤和心血管疾病的发病率和死亡率。这对儿童尤其重要，他们面临着终身免疫抑制的更大累积负担。据单中心报道，移植受者似乎具有功能耐受性，需要最低限度的免疫抑制或无需免疫抑制。初步数据显示，某些儿科移植受者停用免疫抑制药物是安全的，而且可能比成人更成功。为了最大限度地减少与免疫抑制撤销或最小化相关的风险，定义一种在保持免疫功能的同时促进同种异体移植耐受的免疫表型是至关重要的。我们将重点研究儿童肝和肾移植受者的CD4+CD25+Foxp3+T调节(Treg)细胞的功能，因为这些细胞在各种模型中对诱导和维持同种异体移植耐受至关重要。然而，它们在接受常规“三重”免疫抑制治疗的临床器官移植受者中所扮演的角色却鲜为人知。我们推测，使用基于CNI的免疫抑制可能会损害Foxp3+Tregs的发育和功能；这种功能效应可能是由于CNI不同地影响了Foxp3的两个新发现的化学修饰，即Foxp3甲基化和乙酰化。相反，我们假设接受无CNI免疫抑制的移植受者将表现出增加的Foxp3+Treg数量和/或功能，这是这些表观遗传学改变逆转的结果。因此，我们建议对肾或肝移植受者进行一项横断面研究，这些受者在移植后三年或更长时间内，在基于CNI或非CNI的免疫抑制方面具有稳定的同种异体移植功能。我们将使用外周血来评估CNI是否抑制移植受者的Foxp3+Treg数量和/或功能，以及CNI是否促进Foxp3甲基化，减少Foxp3和组蛋白乙酰化？这些研究将为Foxp3+Treg细胞功能的控制提供洞察力，可能提出未来在体内调节Foxp3功能的潜在分子靶点，并可能在移植领域以外产生重大影响。我们预计，他们还将提供在儿科移植受者CNI最小化影响的后续多中心试验中进行计划的机械性研究所需的关键先导数据。 公共卫生相关性：接受器官移植的患者目前经历了多年良好到极佳的移植物功能和生活质量，但尽管如此，这些移植物通常确实会磨损，患者可能会经历与其维持免疫抑制相关的其他严重疾病。我们推测，移植后广泛使用的某些免疫抑制药物可能会损害调节性T细胞的功能，否则可能会在免疫抑制最少或明显减少的情况下促进植入。我们对免疫抑制对调节性T细胞的影响的研究可能会对移植后的免疫抑制治疗产生革命性的影响，并从长远来看降低患者的发病率和移植物功能障碍。

DESCRIPTION (provided by investigator): The Children's Hospital of Philadelphia (CHOP) contributes substantially to the local economy. In 2008, CHOP's operations created and supported over 16,882 jobs in the region, and CHOP's total economic impact was over $5.9 billion. Moreover, through a combination of private donations, NIH funding, and allocations from its hospital operations, CHOP receives more total research support than any other children's hospital in the US -- $180 million in fiscal year 2007-2008. The current application will create or retain 6 jobs. We wish to improve outcomes for transplant recipients by optimizing the current patient care. Solid organ transplant recipients face long-term morbidity and mortality from infections, renal dysfunction, malignancy and cardiovascular disease. This is of particular importance in children, who face a greater cumulative burden of life-long immunosuppression. Single centers have reported transplant recipients who appear functionally tolerant and require minimal or no immunosuppression. Initial data indicate immuno-suppression withdrawal in certain pediatric transplant recipients can be done safely and perhaps more successfully than in adults. To minimize risks associated with immunosuppression withdrawal or minimization, the definition of an immune phenotype that promotes allograft tolerance while maintaining immune competence is critical. We will focus on CD4+CD25+Foxp3+ T regulatory (Treg) cell function in pediatric liver and kidney transplant recipients since these cells are critical to induction and maintenance of allograft tolerance in various models. However, their role in clinical organ transplant recipients treated with regular "triple" immunosuppression is little understood. We hypothesize that use of CNI-based immunosuppression may impair the development and function of Foxp3+ Tregs; the functional effects may result from CNI differentially affecting two newly recognized chemical modifications of Foxp3, namely Foxp3 methylation and acetylation. In contrast, we hypothesize that transplant recipients on CNI-free immunosuppression will show increased Foxp3+ Treg numbers and/or function as a result of reversal of these epigenetic changes. Accordingly, we propose a cross-sectional study of renal or liver transplant recipients who are three or more year's post- transplant and have stable allograft function on CNI-based or CNI-free immunosuppression. We will use peripheral blood to assess whether CNI use depresses Foxp3+ Treg numbers and/or function, and whether CNI use promotes Foxp3 methylation and decreases Foxp3 and histone acetylation in transplant recipients? These studies will provide insights into the control of Foxp3+ Treg cell function, may suggest potential future molecular targets to modulate Foxp3 function in vivo, and will likely have major impact beyond the transplant field. We anticipate that they will also provide the key pilot data required for planned mechanistic studies in a follow-up multi-center trial of the effects of CNI minimization in pediatric transplant recipients. PUBLIC HEALTH RELEVANCE: Patients receiving organ transplants currently experience many years of good to excellent graft function and quality of life, but nevertheless these grafts typically do wear out and patients may experience additional serious diseases related to their maintenance immunosuppression. We hypothesize that certain immunosuppressive drugs widely used post-transplant may impair the functions of regulatory T cells that might otherwise promote engraftment with minimal or markedly reduced immunosuppression. Our studies of the effects of immunosuppression on regulatory T cells may revolutionize immunosuppressive therapy post- transplant and decrease patient morbidity and graft dysfunction long-term.