Calcineurin Inhibitor Minimization And Foxp3+ Tregs Post-Transplant

描述（由研究者提供）：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，通过私人捐赠、国家卫生研究院资助和医院运营拨款的结合，CHOP获得的研究支持总额比美国任何其他儿童医院都多——2007-2008财政年度为1.8亿美元。当前应用程序将创建或保留6个工作。我们希望通过优化目前的患者护理来改善移植受者的预后。实体器官移植受者面临感染、肾功能障碍、恶性肿瘤和心血管疾病的长期发病率和死亡率。这对儿童尤其重要，因为他们面临更大的终身免疫抑制累积负担。单个中心已经报道移植受者表现出功能耐受，并且需要很少或不需要免疫抑制。初步数据表明，某些儿童移植受者的免疫抑制戒断可以安全完成，而且可能比成人更成功。为了最大限度地减少与免疫抑制退出或最小化相关的风险，在维持免疫能力的同时促进同种异体移植物耐受的免疫表型的定义至关重要。我们将重点关注CD4+CD25+Foxp3+ T调节（Treg）细胞在儿童肝脏和肾脏移植受者中的功能，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，它们在常规“三重”免疫抑制治疗的临床器官移植受者中的作用尚不清楚。我们假设使用基于cni的免疫抑制可能会损害Foxp3+ Tregs的发育和功能；功能影响可能是由于CNI不同程度地影响了Foxp3的两种新认识的化学修饰，即Foxp3的甲基化和乙酰化。相反，我们假设接受无cni免疫抑制的移植受者将显示Foxp3+ Treg数量和/或功能增加，这是这些表观遗传变化逆转的结果。因此，我们建议对移植后三年或三年以上且同种异体移植功能稳定的肾或肝移植受者进行基于或不含cni的免疫抑制的横断面研究。我们将使用外周血来评估CNI的使用是否会抑制Foxp3+ Treg的数量和/或功能，以及CNI的使用是否会促进Foxp3甲基化并降低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新的见解，可能为体内调节Foxp3功能提供潜在的未来分子靶点，并可能在移植领域之外产生重大影响。我们预计，他们也将提供关键的试点数据所需的计划机制研究在后续多中心试验CNI最小化对儿童移植受者的影响。

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.