Cytomegalovirus-specific Immune Reconstitution after Hematopoietic Cell Transplantation in the Era of Modern Antiviral Prophylaxis

现代抗病毒预防时代造血细胞移植后巨细胞病毒特异性免疫重建

• 批准号: 10593433
• 负责人: Danniel Zamora
• 金额: $ 15.79万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-07 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10593433
• 关键词: Affect; Allogenic; Animals; Antibodies; Antibody Response; Antibody-mediated protection; Biological Assay; Calcineurin inhibitor; Cells; Cellular Immunity; Cessation of life; Clinical; Cohort Studies; Computing Methodologies; Cyclophosphamide; Cytomegalovirus; Cytomegalovirus Infections; Data; Development; Epitopes; Event; Future; Humoral Immunities; Immune; Immune response; Immunity; Immunologic Monitoring; Immunologics; Immunotherapy; Kinetics; Measures; Methods; Modernization; Outcome; Pattern; Pharmaceutical Preparations; Prevention; Prophylactic treatment; Prospective cohort; Recovery; Regimen; Regulatory T-Lymphocyte; Risk; Role; Serology; Sirolimus; T cell reconstitution; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Technology; Transplant Recipients; Transplantation; Viral; Viral Load result; Virus; advanced analytics; analytical method; antibody detection; antigen-specific T cells; cancer therapy; clinically relevant; clinically significant; combinatorial; exhaustion; graft vs host disease; hematopoietic cell transplantation; human pathogen; immune reconstitution; improved; in vitro Assay; infection risk; neutralizing antibody; novel; pathogen; post-transplant; prevent; prospective; reconstitution; virome

Project Summary/Abstract Cytomegalovirus (CMV) is one of the most important causes of infectious complications following hematopoietic cell transplantation (HCT). Letermovir is an effective antiviral and was recently approved for prophylaxis to prevent CMV reactivation after HCT. Graft-versus-host disease (GVHD) prophylaxis has advanced alongside CMV prophylaxis, but the effects of novel GVHD therapies on infectious complications and immune reconstitution patterns are unclear. Current data suggest that modern GVHD prophylaxis with post-transplantation cyclophosphamide and sirolimus may offer an immunologic advantage over traditional prophylaxis with calcineurin inhibitors. In this proposal, Dr. Zamora will prospectively examine how these GVHD prophylaxis strategies influence CMV-specific T-cell and humoral immunity after HCT, and how these immunological changes can affect overall clinical outcomes. In the first aim of this proposal, Dr. Zamora will examine the effects of viral, host, and transplantation factors, including GVHD prophylaxis, on polyfunctional CMV-specific cellular immune reconstitution. He will use advanced analytical methods to compute polyfunctional T-cell responses and compare differences in immune responses between GVHD prophylaxis regimens. Dr. Zamora will also compare the accuracy of these analytical methods, versus traditional methods of measuring polyfunctionality, in predicting late clinically significant CMV infection after HCT. Furthermore, he will study the immunologic influence of regulatory T cells on the development of polyfunctional T-cell immune reconstitution after HCT and investigate whether this may be affected by the presence or absence of CMV reactivation. Historically, humoral immunity was not felt to be important in CMV prevention after HCT; however, recent animal studies have challenged this notion. Therefore, in the second aim Dr. Zamora will characterize factors influencing functional CMV-specific humoral immune reconstitution after HCT, using state-of-the-art neutralizing antibody and cell-to-cell spread inhibition assays. He will also evaluate the kinetics of CMV-specific antibody responses at the epitope level, using a novel serological profiling technology that can detect antibody responses to thousands of pathogen epitopes (VirScan). Dr. Zamora will investigate the associations of CMV-specific humoral immunity, as measured by these novel immune platforms, with the prevention of late clinically significant CMV reactivation after HCT. Dr. Zamora aims to define CMV-specific T-cell and humoral immune reconstitution kinetics in the current era of advanced GVHD prophylaxis regimens and effective antiviral prophylaxis. This study has the potential to define immunologic parameters to optimize CMV prophylaxis strategies and provide the basis for novel immunotherapy and immune monitoring approaches.

项目总结/摘要 巨细胞病毒（CMV）是造血干细胞移植后感染性并发症的重要原因之一， 细胞移植（HCT）。莱特莫韦是一种有效的抗病毒药物，最近被批准用于预防， 防止HCT后CMV再激活。移植物抗宿主病（GVHD）的预防与 CMV预防，但新的GVHD治疗对感染并发症和免疫重建的影响 模式尚不清楚。目前的数据表明，移植后的现代GVHD预防 环磷酰胺和西罗莫司可以提供优于传统预防的免疫优势， 钙调磷酸酶抑制剂。在这项提案中，萨莫拉博士将前瞻性地研究这些GVHD预防措施 策略影响HCT后CMV特异性T细胞和体液免疫，以及这些免疫学 这些变化可能会影响整体临床结果。 在本提案的第一个目标中，萨莫拉博士将研究病毒、宿主和移植因素的影响， 包括GVHD预防，对多功能CMV特异性细胞免疫重建的影响。他将利用 先进的分析方法来计算多功能T细胞反应，并比较免疫差异 GVHD预防方案之间的反应。萨莫拉博士还将比较这些分析的准确性， 与传统的多功能性测定方法相比， HCT后感染此外，他还将研究调节性T细胞对免疫系统的免疫影响。 HCT后多功能T细胞免疫重建的发展，并研究这是否可能是 受CMV再激活存在与否的影响。 历史上，在HCT后，体液免疫在CMV预防中并不重要;然而，最近的动物实验表明， 研究对这一概念提出了质疑。因此，在第二个目标中，萨莫拉博士将描述影响 HCT后功能性CMV特异性体液免疫重建，使用最先进的中和抗体 和细胞间扩散抑制测定。他还将评估CMV特异性抗体反应的动力学 在表位水平，使用一种新的血清学分析技术，可以检测抗体反应， 成千上万的病原体表位（VirScan）。Zamora博士将研究CMV特异性体液免疫与 通过这些新的免疫平台测量的免疫力，预防晚期临床显著CMV HCT后再激活。 博士Zamora的目标是在当前的时代定义CMV特异性T细胞和体液免疫重建动力学， 先进的GVHD预防方案和有效的抗病毒预防。这项研究有可能定义 免疫学参数，以优化CMV预防策略，并为新型免疫治疗提供基础 和免疫监测方法。