Preventing GVHD by inhibition of alloantigen presentation in the gut

通过抑制肠道内同种抗原的呈现来预防 GVHD

基本信息

批准号：
10652374
负责人：
Geoffrey Roger HILL
金额：
$ 77.78万
依托单位：
FRED HUTCHINSON CANCER CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10652374
关键词：
Acute Graft Versus Host Disease Adrenal Cortex Hormones Alloantigen Allogeneic Bone Marrow Transplantation Antigen Presentation Antigen-Presenting Cells Antigens Aplastic Anemia Automobile Driving Bone Marrow Transplantation Bone marrow failure CD4 Positive T Lymphocytes Calcineurin inhibitor Cellular Indexing of Transcriptomes and Epitopes by Sequencing Clinical Colon Colonoscopy Cyclophosphamide Cytomegalovirus Data Development Disease Emigrations Epithelial Epithelial Cells Equilibrium Event Flow Cytometry Gastrointestinal tract structure Hematopoietic Hematopoietic Neoplasms Immune response Immunity Immunologic Deficiency Syndromes Immunosuppression Inflammation Inflammatory Interruption Intervention Lamina Propria Life Lymphocyte Lymphoid Cell MHC Class II Genes Maintenance Malignant Childhood Neoplasm Malignant Neoplasms Mediating Molecular Mus Natural Killer Cells Non-Malignant Opportunistic Infections Outcome Pathogenicity Pathology Pathway interactions Patients Phase Population Prevention Procedures Prophylactic treatment Refractory Role Sampling Severe Combined Immunodeficiency Signal Transduction Small Intestines Steroids System T cell response T-Lymphocyte Testing Therapeutic Transplant Recipients Transplantation Transplantation Conditioning Work base cell type curative treatments design effector T cell genetic manipulation graft vs host disease graft vs leukemia effect ileum immune reconstitution improved innovation insight intestinal epithelium leukemia leukemia relapse mesenteric lymph node microbiome mortality mouse model novel novel therapeutics pathogen post-transplant pre-clinical preclinical study preservation prevent screening secondary lymphoid organ side effect therapeutic evaluation transcriptome sequencing

项目摘要

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.

抽象的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，同种异体骨髓移植（BMT）是首选的治疗方法对于这些严重的情况。 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 患者会出现严重的 GVHD 这是致命的，尤其是涉及胃肠道时。目前GVHD的预防和治疗依赖于广泛的 T 细胞受到抑制，并且仍然不理想。 T 细胞反应的启动和维持依赖于抗原呈递细胞 (APC) 介导的活性，但引发 GVHD 的 APC 类型和因素目前尚不清楚促进其功能的因素。这是本提案的重点。特别是，我们将在此基础上我们的初步数据检验了致命性急性 GVHD 是在回肠中引发的假设。我们将利用切割- 使用先进的流式细胞术进行边缘机械临床前小鼠研究和平行临床分析， RNASeq 和 REAP/CITE-seq 专注于胃肠道中的抗原呈递，临床识别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。该提案将带来新的、基于抑制疾病发生（即，快速测试预防 GVHD 的治疗方法）同种异体抗原呈递），而不是像目前那样在疾病晚期效应阶段广泛抑制 T 细胞实践。