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

基本信息

批准号：
9062876
负责人：
Sophie Paczesny
金额：
$ 50.58万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9062876
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 HGF gene Health Hematopoietic Neoplasms Histologic IL2RA gene Immunologics Immunosuppressive Agents Immunotherapeutic agent Infection 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 TNFRSF1A gene Testing Therapeutic Therapeutic Intervention Time Toxic effect Translating Tumorigenicity Validation Work alanine aminopeptidase base biomarker panel cancer therapy chronic graft versus host disease clinically relevant conditioning disease diagnosis graft vs host disease hematopoietic cell transplantation high risk improved individualized medicine innovation insight islet mortality novel patient stratification personalized medicine prevent prognostic prognostic value prospective protein biomarkers repository specific biomarkers therapeutic target therapy resistant treatment duration treatment planning

项目摘要

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）：同种异体造血细胞移植（HTC）后的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%）和治疗方法的缺乏之间存在根本性差距并提供生物学相关研究。这一差距代表了一个重要的问题，因为在它被填补之前，治疗将仅限于效应细胞的非特异性类固醇靶向，并且对治疗抵抗性 GVHD 所涉及的免疫途径的理解仍将得到充分探索。我们的长期目标是识别和验证 GVHD 生物标志物，这些生物标志物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。我们本申请的目标是在儿科多中心前瞻性试验中研究经验证的急性和慢性 GVHD 生物标志物。我们的中心假设是血浆生物标志物组可以预测急性和慢性 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，该数据描述了主要是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、皮肤特异性标记物，再生胰岛 3-α，一种胃肠道特异性标记物，可抑制致瘤性 2]，使急性 GVHD 诊断具有良好的特异性和敏感性，并提供包括生存在内的重要预后信息。同样，一组五种慢性 GVHD 蛋白 [由干扰素 γ (CXCL9)、elafin、白细胞介素 2 受体 α、可溶性 B 细胞激活因子 (sBAFF) 和可溶性 CD13 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以及后续发病和死亡风险特别高的儿童，我们就可以提出个性化的治疗计划，如果尽早实施，这些计划将是最有效的。该假设将通过三个具体目标进行测试：1）创建一个儿科多中心临床生物存储库，用于蛋白质组生物标志物。 2) 验证儿科人群中急性和慢性的蛋白质组生物标志物。 3) 创建一个集成的临床有用的 GVHD 蛋白质生物标志物组。这种方法具有创新性，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存储库，可以在 HCT 后并发症方面架起儿科和成人知识和治疗的桥梁。拟议的研究意义重大，因为在症状出现时或更早识别 GVHD 生物标志物组预计将影响我们在开始 GVHD 治疗之前对患者进行风险分层的能力。它还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长期类固醇给药相关的毒性。最终，我们建议发现一种 GVHD 特异性药物，以提高疗效并降低毒性。