Graft versus Host Disease Biomarkers: Prediction of Onset and Response to Therapy

移植物抗宿主疾病生物标志物：预测发病和治疗反应

• 批准号: 7939756
• 负责人: Sophie Paczesny
• 金额: $ 50万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7939756
• 关键词: Acute Graft Versus Host Disease; Address; Aftercare; Allogenic; Area; Award; Biological Assay; Biological Markers; Biopsy; Blood; Blood Cell Count; Blood Cells; Blood Tests; Blood Vessels; Blood specimen; Cardiac; Cell Transplantation; Clinical; Complication; Decision Making; Dendritic Cells; Development; Diagnosis; Diagnostic; Diagnostic or Prognostic Tests; Diagnostic tests; Disease; Disease susceptibility; Enzyme-Linked Immunosorbent Assay; Exhibits; Functional disorder; Future; Gastrointestinal tract structure; Hematological Disease; Hematopoietic; Hematopoietic Stem Cell Transplantation; Immunotherapeutic agent; In complete remission; Liver; Malignant - descriptor; Malignant Neoplasms; Measures; Michigan; Onset of illness; Organ; Organ Transplantation; Pathology; Patients; Phase; Plasma; Predictive Value; Process; Protein Analysis; Proteins; Proteomics; Receiver Operating Characteristics; Regression Analysis; Regulatory T-Lymphocyte; Reporting; Research; Resistance; Respiratory System; Respiratory tract structure; Sampling; Severity of illness; Skin; Symptoms; System; T-Lymphocyte; Technology; Testing; Therapeutic; Transplant Recipients; Transplantation; Universities; Validation; base; clinically relevant; disorder risk; gastrointestinal; graft vs host disease; information gathering; monocyte; mortality; novel; outcome forecast; prognostic; public health relevance; research study; response; statistics; therapy resistant; treatment response

DESCRIPTION (provided by applicant): This application addresses the broad Challenge Area (03) Biomarker Discovery and Validation and the specific Challenge Topic, 03-HL-101: Identify and validate clinically relevant, quantifiable biomarkers of diagnostic and therapeutic responses for blood, vascular, cardiac, and respiratory tract dysfunction. Allogeneic hematopoietic stem cell transplantation is a potentially curative therapy for many malignant diseases but its clinical utility has been impeded by acute graft versus host disease (GVHD). Unfortunately, the diagnosis of acute GVHD is based on clinical criteria that must be confirmed by biopsy of one of three target organs (skin, gastrointestinal (GI) tract, or liver) due to a lack of a validated diagnostic blood test. We recently reported a four biomarker panel that discriminated between patients with and without GVHD that predicted long term survival independently of GVHD severity. This analysis has been extended to identify biomarkers that specifically predict the future development of GVHD in two major GVHD targets, the skin and the GI tract. In a discovery phase, I used an intact-protein-analysis-system (IPAS) to identify new potential biomarkers present in pooled patient plasma from 10 patients collected 14 days prior to the onset of skin- specific GVHD or GI tract-specific GVHD. I identified 16 candidate proteins that were significantly elevated in the plasma of patients that went on to develop GVHD and that could be readily measured by ELISA assays. During this award period, I propose to validate these candidate GVHD biomarkers in plasma samples from approximately 600 allogeneic transplant patients treated at the University of Michigan since 2000. Furthermore, less than half of patients treated with standard frontline treatment for acute GVHD exhibit complete responses. Therefore, I propose to extend this study to the identification and validation of biomarkers that predict the degree of response to GVHD therapy. Using IPAS, I will identify candidate biomarkers elevated in pooled plasma collected 4 weeks after treatment initiation from therapy-resistant patients but not in the plasma of patients who respond to therapy. I will then validate the candidate biomarkers in plasma samples from approximately 300 matched GVHD patient samples pre-treatment and 4 weeks post- treatment. GVHD pathology not only involves soluble factors but also cellular factors. Therefore, I propose as a complementary and alternative approach, to evaluate cellular biomarkers including levels of regulatory T cells, blood dendritic cells, blood monocytes, and subsets of circulating T cells for their capacity to predict GVHD risk and responsiveness to treatment. Specific aim 1 will validate general, skin, and GI-tract GVHD plasma candidate biomarkers, identify and validate cellular biomarkers, and integrate these findings into a cohesive biomarker panel with the greatest predictive potential for future GVHD occurrence. Specific aim 2 will identify and validate plasma and cellular candidates and integrate these biomarkers into a panel that predicts responsiveness to GVHD therapy. PUBLIC HEALTH RELEVANCE: Allogeneic hematopoietic stem cell transplantation is a potentially curative therapy for many malignant diseases whose applicability has been impeded by the development of its most serious complication, acute graft versus host disease (GVHD). Unfortunately there is no validated diagnostic blood test for acute GVHD. Strategies that identify and validate biomarkers of predictive, diagnostic and therapeutic responses for GVHD will allow for better harnessing of treatment in many patients with hematological cancers.

描述（由申请人提供）：本申请涉及广泛的挑战领域 (03) 生物标志物发现和验证以及具体的挑战主题 03-HL-101：识别和验证血液、血管、心脏和呼吸道功能障碍的诊断和治疗反应的临床相关、可量化的生物标志物。异基因造血干细胞移植是许多恶性疾病的潜在治疗方法，但其临床应用受到急性移植物抗宿主病（GVHD）的阻碍。不幸的是，急性 GVHD 的诊断基于临床标准，由于缺乏经过验证的诊断性血液测试，必须通过三个目标器官（皮肤、胃肠道 (GI) 或肝脏）之一的活检来确认。我们最近报道了一个四种生物标志物组，该组可以区分患有和不患有 GVHD 的患者，并预测长期生存，而与 GVHD 严重程度无关。该分析已扩展到识别专门预测皮肤和胃肠道这两个主要 GVHD 目标中 GVHD 未来发展的生物标志物。在发现阶段，我使用完整蛋白质分析系统 (IPAS) 来识别皮肤特异性 GVHD 或胃肠道特异性 GVHD 发病前 14 天收集的 10 名患者的混合患者血浆中存在的新的潜在生物标志物。我鉴定出 16 种候选蛋白，这些蛋白在发生 GVHD 的患者血浆中显着升高，并且可以通过 ELISA 测定轻松测量。在此奖励期间，我建议在来自 2000 年以来在密歇根大学接受治疗的约 600 名同种异体移植患者的血浆样本中验证这些候选 GVHD 生物标志物。此外，接受急性 GVHD 标准一线治疗的患者中不到一半表现出完全缓解。因此，我建议将这项研究扩展到预测 GVHD 治疗反应程度的生物标志物的识别和验证。使用IPAS，我将识别治疗开始后4周从治疗抵抗患者收集的混合血浆中升高的候选生物标志物，但在对治疗有反应的患者的血浆中则没有升高。然后，我将验证治疗前和治疗后 4 周约 300 名匹配的 GVHD 患者样本的血浆样本中的候选生物标志物。 GVHD病理学不仅涉及可溶性因子，还涉及细胞因子。因此，我建议作为一种补充和替代方法，评估细胞生物标志物，包括调节性 T 细胞、血液树突状细胞、血液单核细胞和循环 T 细胞亚群的水平，以评估其预测 GVHD 风险和治疗反应的能力。具体目标 1 将验证一般、皮肤和胃肠道 GVHD 血浆候选生物标志物，识别和验证细胞生物标志物，并将这些发现整合到一个对未来 GVHD 发生具有最大预测潜力的内聚生物标志物组中。具体目标 2 将识别和验证血浆和细胞候选物，并将这些生物标志物整合到预测 GVHD 治疗反应的面板中。 公众健康相关性：同种异体造血干细胞移植是治疗许多恶性疾病的一种潜在疗法，但其适用性因其最严重的并发症——急性移植物抗宿主病（GVHD）的发展而受到阻碍。不幸的是，目前还没有针对急性 GVHD 的有效诊断性血液检测。识别和验证 GVHD 预测、诊断和治疗反应的生物标志物的策略将有助于更好地利用许多血液癌患者的治疗。