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：
10737340
负责人：
Geoffrey Roger HILL
金额：
$ 85.64万
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 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10737340
关键词：
ATAC-seq Acute Graft Versus Host Disease Adrenal Cortex Hormones Affect Alloantigen Allogeneic Bone Marrow Transplantation Antigen Presentation Antigen-Presenting Cells Antigens Aplastic Anemia Bone Marrow Transplantation Bone marrow failure CD4 Positive T Lymphocytes Calcineurin inhibitor Cell Communication Cells Cellular Indexing of Transcriptomes and Epitopes by Sequencing Clinical Cues Cyclophosphamide Cytokine Receptors Cytokine Signaling Cytomegalovirus Data Development Disease Disease Outcome Disparate Epithelial Cells Epithelium Event Flow Cytometry Gastrointestinal tract structure Generations Hematopoietic Hematopoietic Neoplasms Immune Cell Suppression Immune response Immunity Immunologic Deficiency Syndromes Infection Inflammation Inflammatory Interruption Intervention Intestines Life Lymphocyte MHC Class I Genes MHC Class II Genes Maintenance Malignant Childhood Neoplasm Malignant Neoplasms Mediating Modeling Molecular Mus Natural Killer Cells Non-Malignant Opportunistic Infections Outcome Pathogenicity Pathway interactions Patients Peptide Initiation Factors Phase Population Prevention Process Proteins RNA Refractory Resolution Role Sampling Severe Combined Immunodeficiency Small Intestines Steroids System T cell differentiation T cell response T-Lymphocyte Testing Therapeutic Transplant Recipients Transplantation Work XCR1 gene cell type curative treatments cytokine design effective therapy effector T cell gastrointestinal epithelium genetic manipulation graft vs host disease graft vs leukemia effect ileum immune reconstitution improved innovation insight intestinal epithelium leukemia mortality mouse model novel novel therapeutic intervention novel therapeutics pathogen permissiveness post-transplant pre-clinical preclinical study prevent response sequencing platform side effect stem cells therapeutic evaluation

项目摘要

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.

项目概要/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，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，促进其功能的手段有限。这是本提案的重点。特别是，我们将在我们的初步数据检验了回肠上皮 APC 引发致命 Th1 依赖性急性 GVHD 的假设。我们将利用尖端的机械临床前小鼠研究和并行临床分析，使用先进的流式细胞术、单细胞 RNA/CITE-seq 和 ATAC-seq 以及新的空间蛋白质和测序平台重点关注胃肠道中的抗原呈递，确定临床上可处理的途径，以预防致命的急性 GVHD 的发展。此次 R01 更新将继续寻找新的、快速测试的治疗方法基于抑制疾病发生（即同种异体抗原呈递）来预防 GVHD 的方法，而不是与目前的做法相比，在疾病晚期效应阶段广泛抑制 T 细胞。