Calcineurin Inhibitor Minimization And Foxp3+ Tregs Post-Transplant

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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.