Development of Transplant Strategies Uniquely Responsive to the Needs of Children

制定专门满足儿童需求的移植策略

• 批准号: 8039980
• 负责人: Allan D. Kirk
• 金额: $ 149.01万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8039980
• 关键词: Acute; Adolescent; Adult; African; Age; Alloantigen; Allografting; Antibodies; Antigens; Asians; Attention; Behavioral; Beryllium; Biological; Biological Assay; Biopsy; Blood Volume; Cardiovascular system; Caring; Cell Separation; Characteristics; Child; Childhood; Clinical; Clinical Data; Clinical assessments; Complex; Cytomegalovirus; Data; Development; Diagnostic; Disease; Dose; Drug toxicity; Emotional; End stage renal failure; Ensure; Environment; European; Evaluation; Exposure to; Failure; Flow Cytometry; Functional disorder; Genes; Geographic Distribution; Goals; Hispanics; Histology; Human Herpesvirus 4; Immune; Immune Targeting; Immunologic Monitoring; Immunosuppression; Immunosuppressive Agents; In Vitro; Incidence; Individual; Intervention; Investigation; Kidney; Kidney Transplantation; Knowledge; Lead; Life; Longevity; Longitudinal Studies; Major Histocompatibility Complex; Malignant - descriptor; Measures; Medical; Memory; Metabolic; Methods; Morbidity - disease rate; Organ; Organ Transplantation; Outcome; Pathology; Patients; Peripheral; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Physiological; Population; Population Study; Process; Prophylactic treatment; Protocols documentation; Regimen; Research; Risk; Schedule; Screening procedure; Sensitivity and Specificity; Side; Site; Specificity; Staging; Surface; T memory cell; T-Lymphocyte; Testing; Time; Toxic effect; Transcript; Translating; Transplant Recipients; Transplantation; Treatment Protocols; United States; Variant; Viral; Virus Diseases; age group; allograft rejection; base; clinical application; clinical care; clinically relevant; cost; cross reactivity; density; design; drug development; drug sensitivity; early adolescence; experience; follow-up; health care delivery; immune activation; immune function; immunoregulation; implantation; improved; isoimmunity; kidney allograft; novel; pathogen; pathogen exposure; patient population; pediatrician; practical application; prevent; programs; prospective; response; social; tool

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.

描述（由申请人提供）：器官移植是儿童大多数末端器官疾病的首选疗法。成功的移植取决于用多种免疫调节药物治疗以防止排斥反应，但是大多数移植的缺陷是与这些药物相关的毒性的直接结果。在儿童中尤其如此，因为大多数药物方案是在成人临床上开发的，并且在儿童中没有足够的直接研究。重要的是，儿童具有许多生理，免疫学和发育特征，将其与成年人区分开来，这些成年人与发育中不同的免疫反应性和独特的排斥反应相关。这项研究提出了对需要，接受和持久肾移植的儿童的分析。该提议的主要前提是，随着儿童的发展，特别是由于环境病原体暴露的成熟，其免疫调节药物疗法的需求以高度个性化的方式变化。未能针对这些发展变化量身定制疗法会增加药物毒性和排斥的可能性。此外，我们假设可以通过有针对性的免疫评估来预测这些变化，这些评估可以发展为实用的临床工具，以个性化儿童的移植治疗。为了促进这一前提，我们将在三个突出的，繁忙的小儿移植中心同步肾移植护理，并在代表性的多民族患者人群中进行综合的纵向研究。在AIM 1中，我们将定义环境抗原暴露对T细胞表型的影响，并假设T细胞记忆对环境病原体的T细胞记忆加剧了儿童的同种异体免疫反应，增加了他们的排斥风险，并增加了药物不保留的风险。在AIM 2中，我们将在儿童中建立稳定性和排斥反应的转录曲线，假设可以通过分析外围转录体的分析来确定儿童的T细胞库的成熟度，这可以导致诊断工具在给定的时间内为个体儿童量身定制治疗。在AIM 3中，我们将制定一项临床免疫评估计划，重点是最具挑战性的儿科人群，青少年，假设的假设，即客观的生物学评估可以触发医疗和社会干预措施，从而提高非依从性及其后果。该财团将为个性化的，特定儿童的免疫评估和药物开发提供方法。我们将将其应用于标准的免疫方案，但准备将其应用于新颖的疗法中。该提案的相关性是，它将直接促进需要肾脏替代的儿科患者提供医疗保健的改善，并适用于需要其他器官和免疫调节疗法的儿童。