Translating Novel Drug-Targetable Biomarkers to Treat Graft versus Host Disease

项目摘要/摘要 尽管急性移植物抗宿主病(AGVHD)(高达50%)及其相关疾病的发病率很高 异基因造血细胞移植(allo-HCT)后的死亡率/发病率仍然很少 所提供的治疗方法和生物学相关研究。目前的治疗方法仅限于非特异性类固醇 靶向效应细胞。我们的长期目标是识别和验证GVHD生物标记物具有潜在的 风险分层和治疗靶向。在前一个周期中，我们发现：(1)可溶性刺激-2 白介素33(IL-33)诱骗受体(Sst2)，作为治疗耐药移植物抗宿主病和死亡风险的生物标志物 (N.Engl.(2)机制上，我们已经证明在GVHD期间，Sst2由更早的 肠道基质细胞，然后是细胞病变的肠道T效应细胞(TEFs)(科学转化医学， 2015年)；(3)此外，我们还发现Sst2隔离IL-33，限制其对表达 ST2的跨膜分子形式，主要是细胞保护性调节性T细胞(Treg)(科学 转化医学，2015；临床调查洞察杂志，2019)；(4)通过另一种蛋白质组学 胃肠道疾病患者移植后14天样本比对的发现 移植物抗宿主病与非移植物抗宿主病，我们发现了一个表达CD146的T细胞群体，它倾向于Th17和ICOS(可诱导的T细胞 共刺激因子)诱导(《临床调查洞察杂志》，2016)。我们的新假设解决了差距 将以三个特定的目的进行测试：1)阐明细胞和分子机制 抗ST2中和抗体介导的炎症调节；2)实施预期的多中心 将ST2阈值确定为aGVHD预后生物标记物的研究 3)用ICOS/CD28双拮抗剂抑制ICOS/ICOSL通路，以防止和 治疗移植物抗宿主病。拟议的研究意义重大，因为这些研究的影响将是1)风险分层 患者在开始GVHD治疗之前，以及2)开发全新的治疗策略，同时 同时为一种致命的疾病--移植物抗宿主病提供新的生物学见解。

PROJECT SUMMARY/ABSTRACT Despite the high rates of acute graft versus host disease (aGVHD) (up to 50%) and their related mortality/morbidity following allogeneic hematopoietic cell transplantation (allo-HCT), there remains a paucity of therapies and biological correlative studies offered. Current therapies are limited to the nonspecific steroidal targeting of effector cells. Our long-term goal is to identify and validate GVHD biomarkers with the potential for risk stratification and therapeutic targeting. In the previous cycle, we discovered that: (1) soluble STimulation-2 (sST2), the interleukin-33 (IL-33) decoy receptor, as a biomarker for risk of therapy-resistant GVHD and death (N. Engl. J. Med, 2013); (2) Mechanistically, we have shown that during GVHD, sST2 was secreted earlier by intestinal stromal cells and later by cytopathic intestinal T effector cells (Teffs) (Science Translational Medicine, 2015); (3) Furthermore, we have shown that sST2 sequesters IL-33, limiting its availability to T cells expressing the transmembrane molecule form of ST2, mostly cytoprotective regulatory T cells (Tregs) (Science Translational Medicine, 2015; Journal of Clinical Investigation Insights, 2019); (4) Through another proteomics discovery comparing samples at 14 days post-transplantation in patients who develop gastrointestinal (GI) GVHD vs not, we found a T-cell population expressing CD146 that is Th17 prone and ICOS (Inducible T-cell COStimulator)-induced (Journal of Clinical Investigation Insights, 2016). Our new hypotheses address gaps remaining and will be tested with three specific aims: 1) Elucidate the cellular and molecular mechanisms of anti-ST2 neutralizing antibody mediated regulation of inflammation; 2) Implement a prospective multicenter study to determine ST2 threshold as a prognostic biomarker of aGVHD for enabling a biomarker-based preemptive trial; and 3) Inhibit the ICOS/ICOSL pathway with a dual ICOS/CD28 antagonist to prevent and treat aGVHD. The proposed research is significant because the impact of these studies will be 1) to risk stratify patients before initiating GVHD treatment, and 2) to develop entirely novel therapeutic strategies while simultaneously providing novel biological insights into a fatal condition, GVHD.