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：
10204102
负责人：
Geoffrey Roger HILL
金额：
$ 56.29万
依托单位：
FRED HUTCHINSON CANCER RESEARCH 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 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10204102
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 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 Pancytopenia 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.

抽象的血液癌约占所有恶性肿瘤的10％。另外，非恶性骨髓衰竭疾病，例如性贫血或免疫缺陷疾病，例如严重的联合免疫缺陷，威胁生命的疾病和同种异体骨髓移植（BMT）是首选的治疗疗法对于这些严重的条件。 BMT结果受到移植相关并发症的限制，主要是移植物 - 宿主病（GVHD）和机会性感染。实际上，15-20％的BMT患者会出现严重的GVHD 那是致命的，尤其是在涉及胃肠道的情况下。当前的预防和治疗GVHD取决于广泛的抑制T细胞并保持次优。 T细胞响应的启动和维护取决于关于由抗原呈递细胞（APC）介导的活动，但启动GVHD的APC类型和因素目前，促进他们的功能是未知的。这是该提议的重点。特别是，我们将基于我们的初步数据测试了在回肠中启动致命急性GVHD的假设。我们将利用剪裁 - 边缘机械临床前鼠研究，并使用先进的流式细胞仪进行平行的临床分析， rnaseq和Reap/cite-seq专注于胃肠道中的抗原表现，从临床上识别可阻止致命急性GVHD发展的可访问途径，同时允许GVL和病原体在原发性和继发性淋巴器官中启动的特异性免疫力。该提议将导致新的快速测试基于疾病起步的抑制（即同种抗原表现）而不是在疾病的晚期效应阶段，而不是当前实践。