Preventing GVHD by inhibition of alloantigen presentation in the gut

项目摘要/摘要 血癌约占所有恶性肿瘤的10%。此外，非恶性骨髓衰竭 再生障碍性贫血等疾病，或严重联合免疫缺陷等免疫缺陷疾病， 是危及生命的疾病吗？异基因骨髓移植是首选的治疗方法 在这些严重的情况下。骨髓移植的结果受到移植相关并发症的限制，主要是移植物抗- 宿主病(GVHD)和机会性感染。事实上，15%-20%的骨髓移植患者将发展为严重的移植物抗宿主病 这是致命的，特别是涉及胃肠道的时候。目前预防和治疗移植物抗宿主病依赖于广泛的 抑制T细胞，仍然是次优的。T细胞反应的启动和维持依赖于 抗原提呈细胞(APC)介导的活性及引发GVHD的APC类型和因素 促进其功能的活动目前受到限制。这是这项提案的重点。特别是，我们将在我们的 初步数据验证回肠上皮性APC启动致死性Th1依赖性急性移植物抗宿主病的假说。 我们将利用尖端的机械性临床前小鼠研究与平行临床分析，使用先进的 流式细胞术、单细胞RNA/CITE-SEQ和ATAC-SEQ与新的空间蛋白质和测序平台 将重点放在胃肠道的抗原提呈上，找出临床上容易处理的途径，以防止 致死性急性移植物抗宿主病的发生。此次R01更新将继续识别新的、快速测试的治疗方法 预防移植物抗宿主病的方法是基于抑制疾病启动(即同种异体抗原递呈) 而不是像目前的做法那样，在疾病的晚期抑制广泛的T细胞。

PROJECT SUMMARY/ABSTRACT Blood cancers account for approximately 10% of all malignancies. In addition, non-malignant bone marrow failure diseases such as aplastic anaemia, or immunodeficiency diseases such as severe combined immunodeficiency, are life-threatening diseases and allogeneic bone marrow transplantation (BMT) is a preferred curative therapy for these serious conditions. BMT outcomes are limited by transplant related complications, mainly graft-versus- host disease (GVHD) and opportunistic infections. Indeed, 15-20% of BMT patients will develop severe GVHD that is fatal, particularly when involving the GI tract. Current prevention and treatment of GVHD rely on the broad suppression of T cells and remains suboptimal. The initiation and maintenance of T cell responses are dependent on activities mediated by antigen-presenting cells (APC) but the types of APC that initiate GVHD and the factors that promote their function is currently limited. This is the focus of this proposal. In particular, we will build on our preliminary data to test the hypothesis that epithelial APC in the ileum initiate lethal Th1 dependent acute GVHD. We will utilize cutting-edge mechanistic preclinical murine studies with parallel clinical analysis, using advanced flow cytometry, single cell RNA/CITE-seq and ATAC-seq with new spatial protein and sequencing platforms to focus on antigen presentation in the gastrointestinal tract, identifying clinically tractable pathways that will prevent the development of lethal acute GVHD. This R01 renewal will continue to identify new, rapidly testing therapeutic approaches to prevent GVHD based on the inhibition of disease initiation (i.e. alloantigen presentation) rather than broad T cell suppression in the late effector phase of disease, as is current practice.