Development of Transplant Strategies Uniquely Responsive to the Needs of Children

描述（由申请人提供）：器官移植是大多数儿童终末期器官疾病的首选治疗方法。成功的移植取决于各种免疫调节药物的治疗以防止排斥反应，但大多数移植的缺陷是与这些药物相关的毒性的直接结果。这在儿童中尤其如此，因为大多数药物方案是在成人中临床开发的，并且没有在儿童中进行充分的直接研究。重要的是，儿童具有许多生理、免疫和发育特征，将其与成人区分开来，这些特征与发育上不同的免疫反应和独特的排斥表现机制有关。本研究对需要、接受和耐受肾移植的儿童进行了分析。该提案的中心前提是，随着儿童的发育，特别是随着他们的免疫库因环境病原体暴露而成熟，他们对免疫调节药物治疗的需求以高度个性化的方式发生变化。未能针对这些发育变化定制治疗增加了药物毒性和排斥的可能性。此外，我们假设这些变化可以通过有针对性的免疫评估来预测，这些评估可以发展成为实用的临床工具，以个性化儿童移植治疗。为了实现这一前提，我们将在三个突出的、忙碌的儿科移植中心同步肾移植护理，并在一个有代表性的、多种族的患者人群中进行一项综合纵向研究。在目标1中，我们将定义环境抗原暴露对T细胞表型和同种免疫反应性的影响，假设T细胞对环境病原体的记忆增强了儿童的同种免疫反应，增加了排斥反应的风险，并增加了药物不粘附的风险。在目标2中，我们将建立儿童稳定性和排斥反应的转录谱，假设儿童T细胞库的成熟度可以通过分析外周转录体来确定，并且这可以导致诊断工具在给定的时间点为单个儿童定制治疗。在目标3中，我们将制定一项临床免疫评估计划，重点关注最具挑战性的儿科人群，即青少年，假设客观的生物学评价可以引发预防不依从及其后果的医疗和社会干预。该联盟将提供个体化、儿童特异性免疫评估和药物开发的方法。我们将把它应用于标准的免疫方案，但准备将它们应用于新的疗法，因为它们变得可用。该提案的相关性在于，它将直接促进改善需要肾脏替代的儿科患者的医疗保健服务，并适用于需要其他器官和免疫调节治疗的儿童。

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.