Bridging Pediatric and Adult Biomarkers of Graft-Versus-Host-Disease

描述(由申请人提供)：异基因造血细胞移植(HTC)后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%)之间存在根本差距，以及所提供的治疗和生物学相关研究的匮乏。这一空白代表着一个重要的问题，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，而对参与耐药移植物抗宿主病的免疫通路的了解仍然不足。我们的长期目标是识别和验证GVHD生物标记物在成人和儿童人群中具有潜在的风险分层和治疗靶向。 我们在这项应用中的目标是在一项儿科多中心前瞻性试验中研究急性和慢性移植物抗宿主病的有效生物标记物。我们的中心假设是，血浆生物标记物可以预测急性和慢性移植物抗宿主病及其对生存的影响。这一假说是基于我们的初步数据，在以成人为主的人群中表征了一组七种生物标志物[白介素2受体α、肿瘤坏死因子受体1、白介素8、肝细胞生长因子、皮肤特异性标志物弹力素、再生胰岛来源的 3-α，胃肠道特异性标记物和抑制致瘤性2]，使急性移植物抗宿主病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，一组由五种慢性GVHD蛋白[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诱导的单核细胞因子]组成的小组诊断慢性GVHD。这项研究的基本原理是，一旦我们能够确定哪些儿童对传统治疗没有反应，以及哪些儿童随后的发病率和死亡率特别高，我们就可以提出个性化的治疗计划，如果及早推出，这些计划是最有效的。这一假设将以三个具体目标进行检验：1)创建儿科多中心临床-生物信息库 蛋白质组生物标志物。2)验证儿童急性和慢性疾病的蛋白质组生物标志物。3)建立完整的GVHD临床有用的蛋白质生物标志物小组。这种方法是创新的，因为它首次创建了一个包含临床数据和生物标本的大型儿科多中心资料库，这将使儿童和成人的知识和治疗在HCT后并发症方面架起桥梁。这项拟议的研究意义重大，因为在症状出现或更早的时候识别GVHD生物标记物小组，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。它将指导治疗的强度和持续时间，并有助于将与长期服用类固醇相关的毒性降至最低。最终，我们建议发现一种针对GVHD的药物，以提高疗效和降低毒性。

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.