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: 7452760
• 负责人: Allan D. Kirk
• 金额: $ 118.69万
• 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/7452760
• 关键词: Acute; Adolescence; Adolescent; Adult; African; Age; All Sites; Alloantigen; Allografting; Antibodies; Antigens; Asians; Attention; Behavioral; 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; Elements; 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; Invasive; 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; Research; Research Personnel; Risk; Schedule; Screening procedure; Sensitivity and Specificity; Side; Site; Specificity; Staging; Standards of Weights and Measures; Surface; T memory cell; T-Lymphocyte; Testing; Therapeutic immunosuppression; Time; Toxic effect; Transcript; Translating; Transplant Recipients; Transplantation; Treatment Protocols; United States; Variant; Viral; Virus Diseases; age group; base; clinically relevant; cost; cross reactivity; density; design; drug development; drug sensitivity; early childhood; experience; follow-up; health care delivery; immune function; immunoregulation; implantation; improved; isoimmunity; kidney allograft; novel; pathogen; pathogen exposure; 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）：器官移植是大多数儿童终末期器官疾病的首选疗法。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，但大多数移植缺陷是与这些药物相关的毒性的直接结果。对于儿童来说尤其如此，因为大多数药物治疗方案都是在成人中临床开发的，并且在儿童中没有进行足够的直接研究而应用。重要的是，儿童具有许多与成人不同的生理、免疫和发育特征，这些特征在机制上与发育变化的免疫反应和独特的排斥反应有关。本研究对需要、接受和忍受肾移植的儿童进行了分析。该提案的核心前提是，随着儿童的成长，特别是当他们的免疫系统因环境病原体暴露而成熟时，他们对免疫调节药物治疗的需求会以高度个体化的方式发生变化。如果未能针对这些发育变化制定治疗方案，就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，这些评估可以开发成实用的临床工具，为儿童提供个体化的移植治疗。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开展一项综合纵向研究。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会强化儿童的同种免疫反应，增加排斥风险，并增加不依从药物的风险。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外周转录体的分析来确定，这可以产生诊断工具，为个别儿童量身定制治疗方案。给定的时间点。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、青少年，假设客观的生物学评估可以触发医疗和社会干预措施，预防不依从性及其后果。该联盟将提供个性化、针对儿童的免疫评估和药物开发方法。我们会将其应用于标准免疫方案，但准备好将其应用于新疗法（当它们可用时）。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。