Advancing Transplantation Outcomes in Children

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Project Summary/Abstract Renal transplantation is widely recognized as the treatment of choice for children with end stage renal disease (ESRD). The life expectancy benefit is significant and a functioning renal transplant enables children to grow well, develop almost normally and improve their school educational performance levels. However, current data indicate that virtually all grafts in pediatric recipients will eventually fail due to chronic allograft dysfunction, and as such, the goal of preserving long-term allograft function is the key area for future progress. Furthermore, registry data indicate that opportunistic infections are now the most common cause for hospitalization and death in the pediatric population. Little is known about pathogen-specific protective immunity in pediatric recipients who are exposed to multiple novel infectious agents throughout the post-transplant period in the absence of Tmemory. Our approach in this trial is based on the concept that successful preservation of long-term allograft function requires an immunosuppressive regimen that targets donor specific alloantibody (DSA) production while preserving pathogen-specific immunity. We also propose that pediatric recipients require precision tools to monitor, identify and prevent silent subclinical intragraft inflammation/rejection, which is common at early times in the post transplant period. Based on a recent pilot study using de novo Belatacept therapy in combination with an mTOR inhibitor (mTORi) in pediatric recipients, we will test the hypothesis that early introduction of a Belatacept/sirolimus maintenance immunosuppressive regimen is safe and efficacious in children to augment immunoregulation, prevent DSA production and enhance long-term allograft function. EBV seropositive primary renal transplant recipients, aged between 6 and 21 yrs, from eleven experienced pediatric clinical centers will be randomized to receive induction therapy with anti-thymocyte globulin and either Belatacept therapy in combination with sirolimus or remain on standard immunosuppression therapy using tacrolimus and mycophenolate mofetil. Primary endpoint analysis includes de novo DSA development and assessment of allograft function after 36 months of follow up. Associated studies include surveillance monitoring using a novel automated point-of-care urine biomarker assay, and in-depth mechanistic studies on the cellular basis for pathogen-specific immunity and evaluation of functional antibody responses to vaccine. Extensive mechanistic studies will also be performed to assess the impact of Belatacept/mTORi on cellular and humoral alloimmunity and the further development of urinary biomarkers to differentiate subclinical rejection from infection. There are significant unmet clinical needs in pediatric recipients who have unique pathogen-specific and alloimmune responses following transplantation. Overall, the relevance of this proposal is that it builds upon previous trials to test if a novel agent (Belatacept) targets allograft dysfunction; in-depth mechanistic monitoring will allow for the prediction of patient course, and our findings will be applicable to recipients of other solid organ transplants.