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：
8706934
负责人：
Sophie Paczesny
金额：
$ 45.43万
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/8706934
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 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 Malignant Neoplasms 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 innovation insight islet mortality novel prevent prognostic prospective public health relevance repository therapeutic target therapy resistant treatment duration treatment planning tumor necrosis factor alpha receptor

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）：在同种异体造血细胞移植（HTC）之后，急性移植与宿主疾病（GVHD）率（GVHD）率（GVHD）率（GVHD）率（最高50％）之间存在基本差距。该差距代表了一个重要的问题，因为在填充疗法之前，疗法将仅限于效应细胞的非特异性类固醇靶向，并且对耐药GVHD涉及的免疫途径的理解将保持不足。我们的长期目标是识别和验证成人和小儿种群中具有风险分层和治疗靶向的GVHD生物标志物。我们在此应用中的目标是研究儿科多中心前瞻性试验中经过验证的急性和慢性GVHD的生物标志物。我们的中心假设是血浆生物标志物板预测急性和慢性GVHD及其对生存的影响。这一假设是根据我们的初步数据来形成的，该数据表征了一个主要成人人群中七个生物标志物的小组[interleukin-2-受体 - α，肿瘤 - 肿瘤 - 疾病 - 因子 - 触发者-1，白介素-8，肝素生长因子，Elafin，elafin，iSled iSlet-indecifored Marker-Regenerates renfifice Markers-receneners-receneners-receneners-receneners-Isleds terdreders- 3-α，一种胃肠道特异性标记和抑制肿瘤性2]，它允许具有良好特异性和敏感性的急性GVHD诊断，并提供重要的预后信息，包括生存。同样，一组五个慢性GVHD蛋白[由干扰素伽马（CXCL9），Elafin，Interleukin-2-受体 - α，可溶性B细胞激活因子（SBAFF）和可溶性CD13诱导的单算蛋白[Monokine]诊断。这项研究的理由是，一旦我们能够识别出对传统治疗的反应，并且对随后发病和死亡的风险特别高的孩子，我们就可以提出个性化的治疗计划，如果早期引入最有效的情况。该假设将以三个特定的目的进行检验：1）为创建一个儿科多中心生物学存储库蛋白质组学生物标志物。 2）在小儿种群中验证急性和慢性的蛋白质组学生物标志物。 3）创建一个GVHD的临床上有用的临床有用的蛋白质生物标志物面板。这种方法具有创新性，因为它首次创建了大型儿科多中心存储库，其中包含临床数据和生物标本，该存储库将允许在HCT后并发症中弥合儿科和成人知识和治疗学。拟议的研究很重要，因为在症状发作或更早的情况下，鉴定GVHD生物标志物面板有望影响我们在启动GVHD治疗之前对患者进行分层的能力。它将指导治疗的强度和持续时间，并有助于最大程度地减少与慢性类固醇给药相关的毒性。最终，我们建议发现GVHD特异性药物以提高功效和降低毒性。