Development of Transplant Strategies Uniquely Responsive to the Needs of Children

DESCRIPTION (provided by applicant): Organ transplantation is the preferred therapy for most end stage organ diseases in children. Successful transplantation is dependent on treatment with a variety of immunomodulatory drugs to prevent rejection, but most of transplantation's imperfections are a direct result of the toxicities associated with these drugs. This is particularly true in children as most drug regimens are clinically developed in adults and applied without sufficient direct study in children. Importantly, children have numerous physiological, immunological, and developmental characteristics distinguishing them from adults that relate mechanistically to developmentally varied immune responsiveness and unique presentations of rejection. This study proposes an analysis of children requiring, receiving, and enduring renal transplantation. The central premise of the proposal is that as children develop, particularly as their immune repertoire is matured by environmental pathogen exposure, their needs for immunomodulatory drug therapies change in a highly individualized manner. Failure to tailor therapies to these developmental changes increases the likelihood of drug toxicity and rejection. Furthermore, we hypothesize that these changes can be anticipated through targeted immune assessments that can be developed into practical clinical tools to individualize transplant treatments for children. To actuate this premise, we will synchronize renal transplant care at three prominent, busy pediatric transplant centers and carry out an integrated longitudinal, study in a representative, multi-ethnic patient population. In Aim 1, we will define the effects of environmental antigen exposure on T cell phenotype and alloimmune responsiveness hypothesizing that T cell memory to environmental pathogens intensifies a child's alloimmune response, increases their risk of rejection, and increases the risk of drug nonadherence. In Aim 2, we will establish transcriptional profiles of stability and rejection in children hypothesizing that the maturity of a child's T cell repertoire can be determined by analysis of the peripheral transcriptosome and that this can lead to diagnostic tools to tailor therapy to an individual child at a given point in time. In Aim 3, we will develop a program of clinical immune assessment focused on the most challenging pediatric population, adolescents, hypothesizing that objective biological evaluation can trigger medical and social interventions pre-empting nonadherence and its consequences. This consortium will provide methods for individualized, child-specific immune assessment and drug development. We will apply this to standard immune regimens but be prepared to apply them to novel therapies as they become available. The relevance of this proposal is that it will directly facilitate improvements in healthcare delivery to pediatric patients in need of renal replacement, with applicability to children in need of other organs and immunomodulatory therapies in general.