Defining Protective CMV Immunity after Transplantation

定义移植后的保护性 CMV 免疫

基本信息

批准号：
10639833
负责人：
Geoffrey Roger HILL
金额：
$ 75.73万
依托单位：
FRED HUTCHINSON CANCER CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-06 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10639833
关键词：
Address Allogenic Antibodies Antigen Presentation Antigens Antiviral Agents B-Lymphocytes Bone Marrow Stem Cell Transplantation Bone Marrow Transplantation Cell Survival Cell Therapy Cells Cellular Immunity Characteristics Cherry - dietary Clinical Clinical Data Complement Complication Consumption Cytomegalovirus Cytomegalovirus Infections Cytomegalovirus Vaccines Data Development Disease Drug resistance Endothelial Cells Failure Hematopoietic stem cells Human Humoral Immunities IL-6 inhibitor Immune Immune response Immune system Immunity Immunocompromised Host Immunoglobulin G Immunoglobulins Immunology Immunosuppression Impairment Inflammation Interleukin-6 Kidney Knowledge Laboratories Life Link Longevity Mediating Modeling Mus Myelosuppression Natural Killer Cells Organ Outcome Passive Transfer of Immunity Pathway interactions Patient-Focused Outcomes Persons Pre-Clinical Model Preparation Prevention Reagent Recrudescences Reporter Reporting Resistance Risk Sampling Science Seroprevalences Serotyping T cell response T memory cell T-Cell Development T-Lymphocyte Therapeutic Intervention Time Tissues Toxic effect Transplant Recipients Transplantation Transplantation Immunology Viral Viremia Virus Virus Replication arm cell mediated immune response clinically relevant cytokine exhaustion experience graft vs host disease improved improved outcome in vivo inhibiting antibody insight novel pre-clinical preclinical study prevent randomized, clinical trials response restraint seropositive translatable strategy virology

项目摘要

PROJECT SUMMARY/ABSTRACT Cytomegalovirus (CMV) infection is a frequent and life-threatening complication that significantly limits the successful outcome of allogeneic hematopoietic stem cell or bone marrow transplantation (referred to hereafter at BMT). We have recently developed long-desired preclinical (murine) models of CMV reactivation after BMT and show for the first time, that humoral immunity is critical to prevent viral recrudescence. We now demonstrate that either the transfer of immune T cells or strain-specific sera (containing IgG antibody) prevents viral reactivation, viremia, end-organ viral replication and CMV disease during graft-versus-host disease (GVHD). We plan to utilize our unique, but well-established preclinical models to define the impact of protective antibody on the temporal and spatial characteristics of CMV reactivation, dissemination and antigen presentation. Subsequently we will define the interplay of T cell and humoral responses that are required for the durable control of CMV reactivation after BMT. Finally, we will develop clinically tractable pathways to enhance CMV immunity whilst preventing GVHD and associated inflammation, targeting IL-6 inhibition. Our proposed studies will provide critical insights into the immune requirements for effective and long-term control of CMV in recipients with GVHD and/or clinically relevant immune suppression and inflammation that will allow us to optimize CMV immunity in clinical BMT to improve patient outcomes.

项目摘要/摘要巨细胞病毒（CMV）感染是一种频繁且威胁生命的并发症，显着限制了同种异体造血干细胞或骨髓移植的成功结果在BMT）。我们最近开发了BMT后CMV重新激活的长期以来的临床前（鼠）模型并首次表明，体液免疫对于预防病毒复发至关重要。我们现在证明免疫T细胞的转移或应变特异性血清（含有IgG抗体）可以防止病毒在移植物抗宿主病（GVHD）期间，重新激活，病毒血症，末期病毒复制和CMV疾病。我们计划利用我们独特但良好的临床前模型来定义保护性抗体对 CMV重新激活，传播和抗原表现的时间和空间特征。随后，我们将定义持久控制所需的T细胞和体液响应的相互作用 BMT后CMV重新激活。最后，我们将开发可增强CMV免疫力的临床访问途径在防止GVHD和相关的炎症的同时，靶向IL-6抑制作用。我们提出的研究将提供对患有GVHD的受体有效和长期控制CMV的免疫要求的重要见解和/或临床相关的免疫抑制和炎症，这将使我们能够优化CMV免疫力临床BMT改善患者预后。