Preventing GVHD by inhibition of alloantigen presentation in the gut

项目总结/摘要 血癌约占所有恶性肿瘤的10%。此外，非恶性骨髓衰竭 疾病如再生障碍性贫血，或免疫缺陷疾病如严重联合免疫缺陷， 是危及生命的疾病，同种异体骨髓移植（BMT）是优选的治愈性疗法 这些严重的条件。BMT的结果受到移植相关并发症的限制，主要是移植物抗- 宿主疾病（GVHD）和机会性感染。事实上，15-20%的BMT患者将发展为严重的GVHD 这是致命的，特别是当涉及胃肠道时。目前GVHD的预防和治疗依赖于广泛的 抑制T细胞并保持次优。T细胞应答的启动和维持依赖于 对抗原提呈细胞（APC）介导的活动的影响，但启动GVHD的APC类型和 目前促进其功能有限。这是本提案的重点。特别是，我们将建立在我们的 初步数据来检验回肠中的上皮APC引发致死性Th 1依赖性急性GVHD的假设。 我们将利用尖端的机制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，以及新的空间蛋白和测序平台， 专注于胃肠道中的抗原呈递，确定临床上易于处理的途径， 致命的急性GVHD的发展。此次R 01更新将继续识别新的、快速测试的治疗药物， 基于抑制疾病起始（即同种异体抗原呈递）而不是基于抑制疾病起始（即同种异体抗原呈递）来预防GVHD的方法 而不是广泛的T细胞抑制在疾病的晚期效应阶段，如目前的做法。

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.