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

描述(由申请人提供)：本申请涉及广泛的挑战领域(03)生物标记物的发现和验证，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、可量化的生物标记物。异基因造血干细胞移植是一种潜在的治疗多种恶性疾病的方法，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的诊断是基于临床标准，由于缺乏有效的诊断血液测试，必须通过三个靶器官(皮肤、胃肠道或肝脏)之一的活检来确认。我们最近报道了一个区分GVHD患者和非GVHD患者的四个生物标志物小组，该小组独立于GVHD严重程度预测长期生存。这一分析已经扩展到识别生物标志物，这些生物标志物专门预测GVHD在两个主要GVHD靶点--皮肤和胃肠道--的未来发展。在发现阶段，我使用完整蛋白质分析系统(IPAS)从10名患者的混合血浆中识别新的潜在生物标记物，这些患者是在皮肤特异性GVHD或胃肠道特异性GVHD发病前14天收集的。我确定了16种候选蛋白，这些蛋白在后来发展为移植物抗宿主病的患者的血浆中显著升高，并且可以很容易地通过ELISA法进行测量。在这一获奖期间，我建议在2000年以来密歇根大学治疗的大约600名异基因移植患者的血浆样本中验证这些候选GVHD生物标记物。此外，在接受标准一线治疗的急性移植物抗宿主病患者中，只有不到一半的患者表现出完全反应。因此，我建议将这项研究扩展到识别和验证预测GVHD治疗反应程度的生物标志物。使用IPAS，我将确定在治疗开始后4周从耐药患者收集的混合血浆中升高的候选生物标志物，而不是在对治疗有反应的患者的血浆中。然后，我将在治疗前和治疗后4周对大约300例匹配的GVHD患者的血浆样本中的候选生物标志物进行验证。GVHD的病理不仅涉及可溶性因子，还涉及细胞因子。因此，我建议作为补充和替代方法，评估细胞生物标志物，包括调节性T细胞、树突状细胞、单核细胞和循环T细胞亚群的水平，以预测GVHD风险和对治疗的反应性。具体目标1将验证全身、皮肤和胃肠道GVHD候选生物标记物，识别和验证细胞生物标记物，并将这些发现整合到一个具有最大预测未来GVHD发生潜力的有凝聚力的生物标记物小组中。特定目标2将识别和验证候选血浆和细胞，并将这些生物标记物整合到一个小组中，预测GVHD治疗的反应性。 公共卫生相关性：异基因造血干细胞移植是许多恶性疾病的潜在治疗方法，但其最严重的并发症-急性移植物抗宿主病(GVHD)的发展阻碍了其应用。不幸的是，目前还没有针对急性移植物抗宿主病的有效诊断血液测试。识别和验证GVHD预测、诊断和治疗反应的生物标记物的战略将允许更好地利用许多血液学癌症患者的治疗。

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.