The Impact of Epstein Barr Virus Infection on the Immune Response in Pediatric Transplant Recipients

EB 病毒感染对儿童移植受者免疫反应的影响

• 批准号: 10356207
• 负责人: Olivia M Martinez
• 金额: $ 33.8万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-22 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10356207
• 关键词: Acute; Address; Adult; Allografting; Ancillary Study; Autologous; B-Cell Lymphomas; B-Lymphocytes; Biological Markers; Blood Circulation; Cell physiology; Cells; Cellular Assay; Child; Childhood; Clinical; Clinical Data; Complement; Complex; Cytometry; Data; Databases; Detection; Development; Diagnosis; Disease; Effector Cell; Environment; Epstein-Barr Virus Infections; Exhibits; Flow Cytometry; Frequencies; Genes; Graft Rejection; Graft Survival; Human; Human Herpesvirus 4; Immune; Immune response; Immune system; Immunity; Immunologics; Immunosuppression; Impairment; Individual; Infectious Mononucleosis; Interleukin-10; Interleukin-6; Lesion; Life; Link; Lymphoma; Lymphoproliferative Disorders; Malignant Neoplasms; Mediating; Medical; Morbidity - disease rate; Natural Killer Cells; Opportunistic Infections; Organ; Organ Transplantation; Outcome; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Population; Prevalence; Prevention; Production; Property; Receptor Cell; Recovery; Risk; Sampling; Shapes; Solid; T-Cell Receptor; T-Lymphocyte; TNF gene; Testing; Time; Transplant Recipients; Transplantation; Viral; Viral Load result; Viremia; Virus; Virus Diseases; adaptive immune response; antigen binding; base; cytokine; dimensional analysis; high dimensionality; immunoregulation; improved; infected B cell; infection risk; insight; mortality; neoplastic cell; novel; pathogen; peripheral blood; personalized approach; post-transplant; prevent; response; restoration; seropositive; single cell analysis; therapeutically effective; tumor

7. Project Summary/Abstract Solid organ transplantation has become a leading therapy for children with a variety of end stage organ diseases. However, the immunosuppression required for prevention of graft rejection places transplant recipients at increased risk of serious opportunistic viral infections that can have deleterious effects on graft and patient survival. In pediatric transplant recipients, Epstein Barr virus (EBV)-associated complications are of particular concern. The clinical manifestations of EBV infection are complex and can range from asymptomatic viremia to aggressive B cell lymphomas associated with post-transplant lymphoproliferative disorder (PTLD). A major question in transplantation has been to understand why some children can control EBV infection while others develop serious life-threatening complications. Thus, new strategies are needed to develop more personalized approaches for diagnosis and treatment of pediatric transplant recipients infected with EBV. We hypothesize that EBV infection shapes the post-transplant innate and adaptive immune response in children and that these changes can be exploited to identify unique immune-based signatures that promote functional EBV immunity and long-term graft survival. To test this hypothesis we propose to utilize extra samples collected as part of CTOT-C-06, “Biomarkers for Post-Transplant Lymphoproliferative Disorders in Children” (PI:Esquivel) and to analyze existing data from CTOT-C-02, “Immune Development in Pediatric Transplantation” (PI:Kirk). We have generated strong preliminary data indicating that: 1) EBV viremia is common in the first year post-transplant in pediatric allograft recipients; 2) NK cells and T cells are increased in lesions of EBV+ PTLD lymphomas compared to EBV- B cell lymphomas; 3) a specific subset of NK cells that express NKG2A+ is capable of responding to, and killing, EBV-infected cells; 4) clonally expanded EBV- specific T cells that utilize TCR with shared sequences within the antigen-binding portion can be identified in EBV-infected individuals; and 5) patients with EBV+ B cell lymphomas secrete immunomodulatory cytokines that can influence the host immune response. In the first Aim we mine data previously obtained in CTOT-C- 02 to investigate NK cell phenotypes and T cell signatures in the context of viral infection and clinical outcome. We determine the relationship between NKG2A+ NK cells, viral load, and control of EBV infection and utilize mass cytometry (cytometry time of flight, CyTOF) to obtain a complete phenotype of EBV-reactive NKG2A+ cells. In the second Aim we use single cell assays to link T cell receptor usage and effector phenotype to reveal the signature of EBV-specific T cells associated with immune protection from EBV. In Aim 3 we address the enigma of why many patients who have had immunosuppression halted as a first line response to the diagnosis of EBV+PTLD maintain their allograft without returning to immunosuppression. We use CyTOF to determine whether recovery from EBV+ PTLD in the absence of immunosuppression favors the development of IL-10-producing B regulatory cells. Together, these studies will provide novel mechanistic insights into the immune response to EBV and will facilitate improvements in diagnosis, management and treatment of EBV disease in pediatric transplant recipients.

7。项目摘要/摘要 固体器官移植已成为针对各种末端器官的儿童的领先疗法 疾病。但是，预防移植物所需的免疫抑制需要移植 受到严重机会性病毒感染风险增加的接收者可能会对移植物删除影响 和患者的生存。在小儿移植受者中，爱泼斯坦巴尔病毒（EBV）相关并发症是 特别关心。 EBV感染的临床表现很复杂，范围从 无症状的病毒血症与侵袭性B细胞淋巴瘤与移植后淋巴细胞增生剂有关 障碍（PTLD）。移植的一个主要问题是了解为什么有些孩子可以控制 EBV感染时，而其他人则会发生严重威胁生命的并发症。那需要新的策略才能 开发更多个性化的方法来诊断和治疗小儿移植受者感染的方法 与EBV。我们假设EBV感染塑造了移植后的先天和适应性免疫 儿童的反应，可以探索这些变化以识别独特的基于免疫的特征 促进功能性EBV免疫学和长期移植生存。为了检验这一假设，我们建议使用 作为CTOT-C-06的一部分收集的额外样品，“移植后淋巴细胞增生疾病的生物标志物 在儿童中”（PI：Esquivel），并分析CTOT-C-02的现有数据，“小儿免疫发育 移植”（PI：KIRK）。我们已经产生了强大的初步数据，表明：1）EBV病毒血症是 在小儿同种异体移植接受者转移后第一年常见； 2）NK细胞和T细胞增加 与EBV-B细胞淋巴瘤相比，在EBV+ PTLD淋巴瘤病变中； 3）NK细胞的特定子集 表达NKG2A+能够响应并杀死感染EBV的细胞。 4）克隆扩展的EBV- 可以在抗原结合部分中使用共享序列的TCR的特定T细胞可以在 EBV感染的个体； 5）患有EBV+ B细胞淋巴瘤的患者秘密免疫调节细胞因子 这会影响宿主免疫反应。在第一个目的中，我们挖掘了以前在CTOT-C-获得的数据 02在病毒感染和临床结果的背景下研究NK细胞表型和T细胞特征。 我们确定NKG2A+ NK细胞，病毒载荷和控制EBV感染之间的关系并利用 质量细胞仪（飞行的细胞仪时间，cytof）以获得EBV反应性NKG2A+的完整表型 细胞。在第二个目的中，我们使用单细胞测定将T细胞受体使用和效应器表型联系起来 揭示与EBV免疫保护有关的EBV特异性T细胞的特异性T细胞的特征。在目标3中我们 解决了为什么许多接受免疫抑制的患者停止作为对第一行的反应的原因 EBV+PTLD的诊断可维持同种异体移植，而无需恢复免疫抑制。我们使用cytof 确定在没有免疫抑制的情况下从EBV+ PTLD中恢复是否有利于 开发IL-10产生的B调节细胞。这些研究将共同​​提供新颖的机械 洞悉对EBV的免疫反应，并将促进诊断，管理和 小儿移植受者的EBV疾病的治疗。

项目成果

Malnutrition and immune cell subsets in children undergoing kidney transplantation.

• DOI: 10.1111/petr.14371
• 发表时间: 2022-12
• 期刊: PEDIATRIC TRANSPLANTATION
• 影响因子: 1.3
• 作者: Shaw, Brian, I;Lee, Hui-Jie;Ettenger, Robert;Grimm, Paul;Reed, Elaine F.;Sarwal, Minnie;Stempora, Linda;Warshaw, Barry;Zhao, Congwen;Martinez, Olivia M.;MacIver, Nancie J.;Kirk, Allan D.;Chambers, Eileen T.
• 通讯作者: Chambers, Eileen T.