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.

项目摘要/摘要 造血后，巨细胞病毒（CMV）是传染病并发症的最重要原因之一 细胞移植（HCT）。 Letermovir是一种有效的抗病毒，最近被批准用于预防 防止HCT后CMV重新激活。移植物抗宿主病（GVHD）预防已与 CMV预防，但新型GVHD疗法对感染并发症和免疫重构的影响 模式不清楚。当前的数据表明，现代GVHD预防后进行移植后进行 环磷酰胺和西罗莫司可能比传统预防具有免疫学优势 钙调蛋白抑制剂。在该提案中，Zamora博士将前瞻性地研究这些GVHD预防 策略影响HCT后CMV特异性T细胞和体液免疫，以及这些免疫学如何 变化会影响整体临床结果。 在该提案的第一个目的中，Zamora博士将研究病毒，宿主和移植因子的影响， 包括预防GVHD，在多功能CMV特异性细胞免疫重构上。他会使用 高级分析方法来计算多功能T细胞反应并比较免疫的差异 GVHD预防方案之间的反应。 Zamora博士还将比较这些分析的准确性 在预测晚期临床意义的CMV方面 HCT后感染。此外，他将研究调节性T细胞对 HCT之后的多功能T细胞免疫重建的发展，并调查是否可能是 受CMV重新激活的存在或不存在。 从历史上看，在HCT之后的CMV预防中，体液免疫并不重要。但是，最近动物 研究挑战了这一观念。因此，在第二个目标中，扎莫拉博士将表征影响的因素 HCT后，使用最新的中和抗体功能性CMV特异性的体液重建 和细胞间扩散抑制测定法。他还将评估CMV特异性抗体反应的动力学 在表位水平上，使用一种新型的血清学分析技术，可以检测到对 成千上万的病原体表位（VirScan）。 Zamora博士将调查CMV特异性体液的关联 通过这些新型免疫平台测量的免疫力，预防晚期临床意义的CMV HCT后重新激活。 Zamora博士的目的是定义CMV特异性的T细胞和体液免疫重建动力学 晚期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疗法提供基础 和免疫监测方法。