Preventing GVHD by inhibition of alloantigen presentation in the gut

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 促进其功能的物质目前尚不清楚。这是本提案的重点。特别是，我们将建立在 我们的初步数据，以测试致命的急性GVHD是在回肠发起的假设。我们将利用切割- 边缘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， RNASeq和REAP/CITE-seq专注于胃肠道中的抗原呈递， 易于处理的途径，将防止致命的急性GVHD的发展，同时允许GVL和病原体- 在初级和次级淋巴器官中启动的特异性免疫。该提案将导致新的， 快速测试基于抑制疾病起始（即， 同种异体抗原呈递），而不是目前在疾病的晚期效应期广泛的T细胞抑制， 实践

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 unknown. This is the focus of this proposal. In particular, we will build on our preliminary data to test the hypothesis that lethal acute GVHD is initiated in the ileum. We will utilize cutting- edge mechanistic preclinical murine studies with parallel clinical analysis, using advanced flow cytometry, RNASeq, and REAP/CITE-seq to focus on antigen presentation in the gastrointestinal tract, identifying clinically tractable pathways that will prevent the development of lethal acute GVHD, whilst permitting GVL and pathogen- specific immunity that are initiated in primary and secondary lymphoid organs. The proposal will lead to 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.