Advancing Transplantation Outcomes in Children

提高儿童移植效果

• 批准号: 10647772
• 负责人: David M. Briscoe
• 金额: $ 262.35万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-07 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10647772
• 关键词: 2019-nCoV; Acute; Address; Adopted; Adult; Age; Allografting; Antibody Response; Antithymoglobulin; Area; Binding; Biological Assay; Biological Markers; Biopsy; Caring; Cell Communication; Cells; Cessation of life; Child; Childhood; Chronic; Clinical; Clinical Trials; Collaborations; Creatinine; Data; Databases; Development; Diagnostic; Donor person; Education; End stage renal failure; Enrollment; Evaluation; Exposure to; Failure; Functional disorder; Future; Genes; Genomics; Genotype; Goals; Graft Survival; Helper-Inducer T-Lymphocyte; Hospitalization; Human Herpesvirus 4; Immune; Immune response; Immunity; Immunobiology; Immunosuppression; Infection; Infectious Agent; Inflammation; Isoantibodies; Kidney Transplantation; Knowledge; Laboratories; Life; Life Expectancy; Living Donors; Maintenance; Maintenance Therapy; Mediating; Memory B-Lymphocyte; Monitor; Morbidity - disease rate; Neoadjuvant Therapy; Opportunistic Infections; Organ Transplantation; Outcome; Patients; Pattern; Performance; Pilot Projects; Population; Process; Production; Proteins; Randomized; Regimen; Renal function; Research Personnel; Risk; Schools; Signal Pathway; Sirolimus; Solid; Survival Rate; T-Lymphocyte; Tacrolimus; Testing; Therapeutic Agents; Therapeutic immunosuppression; Transplant Recipients; Transplantation; Transplantation Immunology; Urine; Vaccines; Virus; Virus Diseases; aged; allograft rejection; arm; clinical center; clinically significant; data registry; efficacy evaluation; experience; follow-up; genome-wide; graft function; immunoregulation; improved; innovation; insight; isoimmunity; mTOR Inhibitor; mortality; mycophenolate mofetil; novel; novel therapeutics; novel virus; open label; pathogen; pediatric patients; point of care; post-transplant; prediction algorithm; preservation; prevent; primary endpoint; response; seropositive; standard of care; tool; transcriptomics; transplant centers; treatment arm; treatment choice; two-arm trial; urinary; vaccine-induced antibodies; virtual

Project Summary/Abstract Renal transplantation is widely recognized as the treatment of choice for children with end stage renal disease (ESRD). The life expectancy benefit is significant and a functioning renal transplant enables children to grow well, develop almost normally and improve their school educational performance levels. However, current data indicate that virtually all grafts in pediatric recipients will eventually fail due to chronic allograft dysfunction, and as such, the goal of preserving long-term allograft function is the key area for future progress. Furthermore, registry data indicate that opportunistic infections are now the most common cause for hospitalization and death in the pediatric population. Little is known about pathogen-specific protective immunity in pediatric recipients who are exposed to multiple novel infectious agents throughout the post-transplant period in the absence of Tmemory. Our approach in this trial is based on the concept that successful preservation of long-term allograft function requires an immunosuppressive regimen that targets donor specific alloantibody (DSA) production while preserving pathogen-specific immunity. We also propose that pediatric recipients require precision tools to monitor, identify and prevent silent subclinical intragraft inflammation/rejection, which is common at early times in the post transplant period. Based on a recent pilot study using de novo Belatacept therapy in combination with an mTOR inhibitor (mTORi) in pediatric recipients, we will test the hypothesis that early introduction of a Belatacept/sirolimus maintenance immunosuppressive regimen is safe and efficacious in children to augment immunoregulation, prevent DSA production and enhance long-term allograft function. EBV seropositive primary renal transplant recipients, aged between 6 and 21 yrs, from eleven experienced pediatric clinical centers will be randomized to receive induction therapy with anti-thymocyte globulin and either Belatacept therapy in combination with sirolimus or remain on standard immunosuppression therapy using tacrolimus and mycophenolate mofetil. Primary endpoint analysis includes de novo DSA development and assessment of allograft function after 36 months of follow up. Associated studies include surveillance monitoring using a novel automated point-of-care urine biomarker assay, and in-depth mechanistic studies on the cellular basis for pathogen-specific immunity and evaluation of functional antibody responses to vaccine. Extensive mechanistic studies will also be performed to assess the impact of Belatacept/mTORi on cellular and humoral alloimmunity and the further development of urinary biomarkers to differentiate subclinical rejection from infection. There are significant unmet clinical needs in pediatric recipients who have unique pathogen-specific and alloimmune responses following transplantation. Overall, the relevance of this proposal is that it builds upon previous trials to test if a novel agent (Belatacept) targets allograft dysfunction; in-depth mechanistic monitoring will allow for the prediction of patient course, and our findings will be applicable to recipients of other solid organ transplants.

项目概要/摘要 肾移植被广泛认为是终末期肾病儿童的首选治疗方法 疾病（终末期肾病）。预期寿命的好处是显着的，功能正常的肾移植使 儿童成长良好、发育几乎正常并提高他们的学校教育表现水平。 然而，目前的数据表明，几乎所有儿科受者的移植物最终都会因慢性病而失败。 同种异体移植物功能障碍，因此，保持长期同种异体移植物功能的目标是 未来的进展。此外，登记数据表明，机会性感染现在是最常见的 儿科人群住院和死亡的原因。对病原体特异性知之甚少 整个过程中暴露于多种新型传染源的儿科接受者的保护性免疫力 移植后缺乏 T 记忆的时期。我们在这次试验中的方法基于以下概念 成功保存长期同种异体移植功能需要免疫抑制方案 靶向供体特异性同种抗体（DSA）的产生，同时保留病原体特异性免疫力。我们也 提议儿科接受者需要精密工具来监测、识别和预防无症状的亚临床 移植物内炎症/排斥，这在移植后早期很常见。基于一个 最近的试点研究使用从头 Belatacept 疗法联合 mTOR 抑制剂 (mTORi) 对于儿科接受者，我们将检验以下假设：早期引入贝拉西普/西罗莫司维持治疗 免疫抑制方案对儿童来说是安全有效的，可增强免疫调节，预防 DSA 生产和增强长期同种异体移植功能。 EBV 血清阳性原发肾移植受者， 来自 11 个经验丰富的儿科临床中心的年龄在 6 至 21 岁之间的儿童将被随机分配接受 抗胸腺细胞球蛋白诱导治疗以及贝拉西普联合西罗莫司或 继续使用他克莫司和吗替麦考酚酯进行标准免疫抑制治疗。基本的 终点分析包括从头 DSA 开发和 36 个月后同种异体移植功能的评估 的跟进。相关研究包括使用新型自动化护理点尿液进行监测 生物标志物测定，以及对病原体特异性免疫和细胞基础的深入机制研究 评估功能性抗体对疫苗的反应。广泛的机制研究也将 进行评估 Belatacept/mTORi 对细胞和体液同种免疫的影响以及进一步 开发尿液生物标志物以区分亚临床排斥反应和感染。有显着的 具有独特病原体特异性和同种免疫反应的儿科受者的临床需求未得到满足 移植后。总体而言，该提案的相关性在于它建立在之前的试验的基础上，以测试是否 一种针对同种异体移植功能障碍的新型药物（Belatacept）；深入的机械监测将允许 预测患者病程，我们的研究结果将适用于其他实体器官移植的受者。