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

项目总结/摘要 尽管急性移植物抗宿主病（aGVHD）的发生率很高（高达50%）， 尽管异基因造血细胞移植（allo-HCT）后的死亡率/发病率， 提供的治疗和生物学相关研究。目前的治疗方法仅限于非特异性类固醇 靶向效应细胞。我们的长期目标是鉴定和验证GVHD生物标志物， 风险分层和治疗靶向。在上一个周期中，我们发现：（1）可溶性STimulation-2 白细胞介素-33（IL-33）诱饵受体（sST 2）作为耐药性GVHD和死亡风险的生物标志物 （N. Engl. J. Med，2013）;（2）从机制上讲，我们已经表明，在GVHD期间，sST 2较早地由GVHD分泌。 肠基质细胞和后来的致细胞病变的肠T效应细胞（Tefs）（ScienceTranslationalMedicine， （3）此外，我们已经表明sST 2螯合IL-33，限制其对表达IL-33的T细胞的可用性， ST 2的跨膜分子形式，主要是细胞保护性调节性T细胞（T细胞）（Science 转化医学，2015;临床研究洞察杂志，2019）;（4）通过另一种蛋白质组学 发现比较移植后14天发生胃肠道（GI）疾病的患者的样本 GVHD与非GVHD相比，我们发现了表达CD 146的T细胞群，其是Th 17倾向的和ICOS（诱导性T细胞 COStimulator）诱导（Journal of Clinical Investigation Insights，2016）。我们的新假设解决了 剩余的，并将测试与三个具体目标：1）阐明细胞和分子机制， 抗ST 2中和抗体介导的炎症调节; 2）实施前瞻性多中心 确定ST 2阈值作为aGVHD预后生物标志物的研究， 抢先试验;和3）用双重ICOS/CD 28拮抗剂抑制ICOS/ICOSL途径，以预防和 治疗aGVHD。拟议的研究是重要的，因为这些研究的影响将是1）风险分层 在开始GVHD治疗之前，2）开发全新的治疗策略， 同时提供了一个新的生物学见解致命的条件，移植物抗宿主病。

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.