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. 项目总结/摘要 实体器官移植已成为儿童多种终末期器官的主要治疗方法 然而，预防移植排斥所需的免疫抑制则需要进行移植。 受者遭受严重机会性病毒感染的风险增加，这可能对移植物产生有害影响 在儿科移植受者中，EB 病毒 (EBV) 相关的并发症是 EBV 感染的临床表现非常复杂，范围广泛。 无症状病毒血症至与移植后淋巴增殖相关的侵袭性 B 细胞淋巴瘤 移植中的一个主要问题是理解为什么有些孩子可以控制。 EBV 感染而其他人则出现严重危及生命的并发症，因此需要新的策略来治疗。 开发更个性化的方法来诊断和治疗感染的儿科移植受者 我们认为 EBV 感染会影响移植后的先天性和适应性免疫。 儿童的反应，并且可以利用这些变化来识别独特的基于免疫的特征 促进功能性 EBV 免疫和长期移植物存活 为了检验这一假设，我们建议利用。 作为 CTOT-C-06“移植后淋巴增殖性疾病的生物标志物”的一部分收集的额外样本 儿童”（PI：Esquivel）并分析 CTOT-C-02“儿科免疫发展”的现有数据 移植”（PI：Kirk）。我们已经生成了强有力的初步数据，表明：1) EBV 病毒血症是 儿童同种异体移植受者移植后第一年常见；2) NK 细胞和 T 细胞增加； 与 EBV- B 细胞淋巴瘤相比，EBV+ PTLD 淋巴瘤的病变中存在特定的 NK 细胞亚群； 表达 NKG2A+ 的细胞能够响应并杀死 EBV 感染的细胞；4) 克隆扩增的 EBV- 利用抗原结合部分内具有共享序列的 TCR 的特定 T 细胞可以在 EBV感染者；5) EBV+ B细胞淋巴瘤患者分泌免疫调节细胞因子 在第一个目标中，我们挖掘之前在 CTOT-C- 中获得的数据。 02 研究病毒感染和临床结果背景下的 NK 细胞表型和 T 细胞特征。 我们确定 NKG2A+ NK 细胞、病毒载量和 EBV 感染控制之间的关系并利用 质谱流式细胞仪（细胞飞行时间细胞术，CyTOF）以获得 EBV 反应性 NKG2A+ 的完整表型 在第二个目标中，我们使用单细胞测定将 T 细胞受体的使用和效应表型联系起来。 在目标 3 中，我们揭示了与 EBV 免疫保护相关的 EBV 特异性 T 细胞的特征。 解决了为什么许多接受过免疫抑制治疗的患者停止将其作为一线反应的谜团 EBV+PTLD 的诊断维持其同种异体移植而不返回免疫抑制。 确定在没有免疫抑制的情况下从 EBV+ PTLD 中恢复是否有利于 产生 IL-10 的 B 调节细胞的开发将提供新的机制。 深入了解 EB 病毒的免疫反应，将有助于改进诊断、管理和治疗 儿科移植受者的 EBV 疾病的治疗。

项目成果

Malnutrition and immune cell subsets in children undergoing kidney transplantation.

接受肾移植的儿童的营养不良和免疫细胞亚群。

• 发表时间: 2022-12
• 影响因子: 1.3
• 作者: Shaw, Brian I;Lee, Hui;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