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: 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
• 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

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）发病率（高达50%）和相关死亡率（高达50%）之间存在根本差距，并且缺乏治疗和生物相关研究。这一差距代表了一个重要的问题，因为在它被填补之前，治疗将局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涉及的免疫途径的理解仍未得到充分探索。我们的长期目标是确定和验证GVHD生物标志物，在成人和儿童人群中具有风险分层和治疗靶向的潜力。