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

项目摘要/摘要 巨细胞病毒(CMV)是导致造血术后感染并发症的重要原因之一。 细胞移植(HCT)。来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重新激活。移植物抗宿主病(GVHD)的预防随着 CMV是预防的，但新的GVHD疗法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，现代移植物抗宿主病是通过移植后预防的 环磷酰胺和西罗莫司可能提供比传统预防方法更好的免疫学优势 钙调神经磷酸酶抑制剂。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 变化可能会影响总体临床结果。 在这项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。他将使用 计算多功能T细胞应答并比较免疫差异的高级分析方法 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 预测晚期临床显著CMV的方法，与传统的多功能测量方法相比 HCT后感染。此外，他还将研究调节性T细胞对 HCT后多功能T细胞免疫重建的研究进展 受存在或不存在CMV重新激活的影响。 从历史上看，体液免疫并不被认为是预防HCT后CMV的重要因素；然而，最近的动物 研究对这一观念提出了挑战。因此，在第二个目标中，萨莫拉博士将描述影响因素 使用最先进的中和抗体，实现HCT后CMV特异性体液免疫的功能性重建 细胞间扩散抑制试验。他还将评估巨细胞病毒特异性抗体反应的动力学。 在表位水平上，使用一种新的血清学图谱技术，可以检测抗体对 数千个病原体表位(VirScan)。萨莫拉博士将研究巨细胞病毒特异性体液与 通过这些新的免疫平台测量的免疫力，以及预防晚期临床显著CMV Hct后重新激活。 Zamora博士的目标是定义当前时代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 优化巨细胞病毒预防策略的免疫学参数，为新型免疫治疗提供依据 和免疫监测方法。

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.