Bridging Pediatric and Adult Biomarkers of Graft-Versus-Host-Disease

桥接儿童和成人移植物抗宿主疾病的生物标志物

• 批准号: 8842670
• 负责人: Sophie Paczesny
• 金额: $ 45.89万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8842670
• 关键词: Acute; Acute Graft Versus Host Disease; Adult; Affect; Aftercare; Age; Allogenic; Alpha Interleukin 2 Receptor; B-Lymphocytes; Biological; Biological Markers; Biological Response Modifier Therapy; Biology; Biopsy; Blood; Blood Tests; Bone Marrow; CXCL9 gene; Cessation of life; Child; Childhood; Chronic; Clinic; Clinical; Clinical Data; Complication; Correlative Study; Data; Diagnosis; Diagnostic; Disease; Effectiveness; Effector Cell; Evaluation; Functional disorder; Gastrointestinal tract structure; Gene Proteins; Goals; Health; Hematopoietic Neoplasms; Hepatocyte Growth Factor; Histologic; IL2RA gene; Immunologics; Immunosuppressive Agents; Immunotherapeutic agent; Infection; Interleukin 2 Receptor; Interleukin-8; Intestines; Knowledge; Life; Liver; Malignant Childhood Neoplasm; Measures; Morbidity - disease rate; Multicenter Trials; Natural regeneration; Organ; Outcome; PI3 gene; Pathway interactions; Patients; Pharmaceutical Preparations; Plasma; Population; Process; Proteins; Proteomics; Regimen; Research; Resistance; Risk; Role; Safety; Sampling; Sensitivity and Specificity; Severities; Skin; Small Inducible Cytokine B9; Specimen; Steroids; Stratification; Surrogate Endpoint; Symptoms; Testing; Therapeutic; Therapeutic Intervention; Time; Toxic effect; Translating; Tumorigenicity; Validation; Work; alanine aminopeptidase; base; cancer therapy; chronic graft versus host disease; clinically relevant; conditioning; disease diagnosis; graft vs host disease; hematopoietic cell transplantation; high risk; human TNFRSF1A protein; improved; individualized medicine; innovation; insight; islet; mortality; novel; personalized medicine; prevent; prognostic; prognostic value; prospective; repository; therapeutic target; therapy resistant; treatment duration; treatment planning; tumor necrosis factor alpha receptor

DESCRIPTION (provided by applicant): A fundamental gap exists between acute graft versus host disease (GVHD) rates (up to 50%) and the related mortality (up to 50%) following allogeneic hematopoietic cell transplantation (HTC) and the paucity of therapies and biological correlative studies offered. This gap represents an important problem, because until it is filled, therapies will be limited to the nonspecific steroidal targeting of effector cells, and the understanding of the immunologic pathways involved in therapy-resistant GVHD will remain underexplored. Our long-term goal is to identify and validate GVHD biomarkers with the potential for risk stratification and therapeutic targeting in both adult and pediatric population. Our objective in this application is to investigate validated biomarkers of acute and chronic GVHD in a pediatric multicenter prospective trial. Our central hypothesis is that plasma biomarker panels predict acute and chronic GVHD and their impact on survival. This hypothesis was formed based on our preliminary data characterizing a panel of seven biomarkers in a predominantly adult population [interleukin-2- receptor-alpha, tumor-necrosis-factor-receptor-1, interleukin-8, hepatocyte growth factor, elafin, a skin-specific marker, regenerating islet-derived 3-alpha, a gastro-intestinal specific marker, and suppression of tumorigenicity 2] that allows acute GVHD diagnosis with good specificity and sensitivity and provides important prognostic information including survival. Similarly, a panel of five chronic GVHD proteins [monokine induced by interferon-gamma (CXCL9), elafin, interleukin-2-receptor-alpha, soluble B-cell-activating factor (sBAFF), and soluble CD13] diagnoses chronic GVHD. The rationale for this study is that once we are able to identify children who will not respond to traditional treatments and who are at particularly high risk for subsequent morbidity and mortality, we can propose personalized treatment plans that are most effective if introduced early. This hypothesis will be tested with three specific aims: 1) Create a pediatric multicenter clinic-biological repository for proteomic biomarkers. 2) To validate proteomic biomarkers of acute and chronic in the pediatric population. 3) Create an integrated clinically useful protein biomarker panel of GVHD. This approach is innovative because it creates for the first time a large pediatric multicenter repository containing both clinical data and bio specimens that will allow bridging pediatric and adult knowledge and therapeutics in complications post-HCT. The proposed research is significant because the identification of GVHD biomarker panels at symptom onset or earlier is expected to impact our ability to risk stratify patients before initiating GVHD treatment. It will lso guide the intensity and duration of treatment, and help minimize the toxicity associated with chronic steroid administration. Ultimately, we propose the discovery of a GVHD-specific drug to increase efficacy and lower toxicity.

描述（由申请人提供）：在异基因造血细胞移植（HTC）后急性移植物抗宿主病（GVHD）发生率（高达50%）和相关死亡率（高达50%）之间存在根本性差距，并且缺乏治疗和生物学相关研究。这一差距代表了一个重要的问题，因为直到它被填补，治疗将限于效应细胞的非特异性类固醇靶向，和耐药GVHD中涉及的免疫途径的理解将继续探索不足。我们的长期目标是鉴定和验证GVHD生物标志物，其具有在成人和儿童人群中进行风险分层和治疗靶向的潜力。 本申请的目的是在儿科多中心前瞻性试验中研究急性和慢性GVHD的有效生物标志物。我们的中心假设是，血浆生物标志物面板预测急性和慢性GVHD及其对生存的影响。这一假设是基于我们的初步数据形成的，这些数据表征了主要成年人群中的一组七种生物标志物[白细胞介素-2-受体-α、肿瘤坏死因子-受体-1、白细胞介素-8、肝细胞生长因子、弹性蛋白酶、皮肤特异性标志物、再生胰岛源性 3-α，一种胃肠道特异性标志物，和致瘤性的抑制2]，其允许具有良好特异性和灵敏度的急性GVHD诊断，并提供重要的预后信息，包括存活率。类似地，一组五种慢性GVHD蛋白[由干扰素-γ（CXCL 9）、弹力素、白介素-2-受体-α、可溶性B细胞活化因子（sBAFF）和可溶性CD 13诱导的单核因子]诊断慢性GVHD。这项研究的基本原理是，一旦我们能够识别出对传统治疗没有反应的儿童，以及随后发病率和死亡率特别高的儿童，我们就可以提出个性化的治疗计划，如果早期引入，这些计划是最有效的。这一假设将通过三个具体目标进行检验：1）创建儿科多中心临床生物学知识库， 蛋白质组学生物标志物。2)验证儿科人群急性和慢性蛋白质组学生物标志物。3)创建一个整合的临床有用的GVHD蛋白质生物标志物面板。这种方法是创新的，因为它首次创建了一个包含临床数据和生物样本的大型儿科多中心库，这将允许桥接儿科和成人的知识以及HCT后并发症的治疗方法。拟议的研究是重要的，因为在症状发作或更早时鉴定GVHD生物标志物组预计将影响我们在开始GVHD治疗前对患者进行风险分层的能力。它也将指导治疗的强度和持续时间，并有助于最大限度地减少与慢性类固醇给药相关的毒性。最终，我们提出了一种GVHD特异性药物的发现，以提高疗效和降低毒性。