Development of Transplant Strategies Uniquely Responsive to the Needs of Children

描述(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。成功的移植依赖于各种免疫调节药物的治疗来防止排斥反应，但大多数移植的不完善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都是在成人临床上开发的，在儿童中没有足够的直接研究就应用了。重要的是，儿童有许多不同于成人的生理、免疫和发育特征，这些特征与发育不同的免疫反应和独特的排斥表现有机械联系。这项研究提出了对儿童需要、接受和忍受肾移植的分析。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系统因环境病原体的暴露而成熟，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量身定做治疗方法会增加药物毒性和排斥反应的可能性。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实用的临床工具，为儿童进行个体化的移植治疗。为了实现这一前提，我们将在三个著名的繁忙的儿科移植中心同步进行肾移植护理，并在具有代表性的多种族患者群体中进行综合的纵向研究。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，增加了他们发生排斥反应的风险，并增加了药物不依附的风险。在目标2中，我们将建立儿童稳定性和排斥反应的转录图谱，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，这可以导致诊断工具在给定的时间点为单个儿童量身定做治疗。在目标3中，我们将开发一个临床免疫评估计划，重点放在最具挑战性的儿科人群-青少年身上，假设客观的生物评估可以触发医疗和社会干预，预防不坚持及其后果。该联盟将为个性化、针对儿童的免疫评估和药物开发提供方法。我们将把这一点应用于标准的免疫疗法，但当新疗法出现时，我们准备将它们应用于新疗法。这项建议的相关性在于，它将直接促进改善对需要肾脏置换的儿科患者的医疗保健服务，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.