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治疗儿童各种终末期器官的主要方法 疾病然而，预防移植排斥反应所需的免疫抑制使移植 严重机会性病毒感染风险增加的受体，可能对移植物产生有害影响 患者生存率。在儿科移植受者中，爱泼斯坦巴尔病毒（EBV）相关并发症是 特别关注。EB病毒感染的临床表现是复杂的，可以从 与移植后淋巴组织增生相关的侵袭性B细胞淋巴瘤的无症状病毒血症 疾病（PTLD）。移植中的一个主要问题是理解为什么有些儿童可以控制 EB病毒感染，而其他发展严重危及生命的并发症。因此，需要新的战略， 为儿科移植受者感染的诊断和治疗开发更个性化的方法 关于EBV我们假设EBV感染影响了移植后的先天性和适应性免疫， 这些变化可以用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。为了验证这一假设，我们建议利用 作为CTOT-C-06“移植后增生性疾病的生物标志物”的一部分采集的额外样本 儿童免疫发育”（PI：Esquivel），并分析CTOT-C-02“儿童免疫发育”中的现有数据， 移植”（PI：柯克）。我们已经产生了强有力的初步数据，表明：1）EBV病毒血症是 常见于儿童同种异体移植受者移植后第一年; 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细胞的特定亚群 表达NKG 2A+的细胞能够响应并杀死EBV感染的细胞; 4）克隆扩增的EBV- 利用在抗原结合部分内具有共享序列的TCR的特异性T细胞可以在 EBV感染的个体;和5）EBV+ B细胞淋巴瘤患者分泌免疫调节细胞因子 能够影响宿主免疫反应的病毒在第一个目标中，我们挖掘以前在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。 我们确定了NKG 2A + NK细胞、病毒载量和EBV感染控制之间的关系，并利用 质谱细胞术（细胞术飞行时间，CyTOF），以获得EBV反应性NKG 2A+的完整表型 细胞在第二个目的中，我们使用单细胞测定来将T细胞受体使用和效应子表型联系起来， 揭示了与EBV免疫保护相关的EBV特异性T细胞的特征。在目标3中， 解决了为什么许多接受免疫抑制的患者停止作为一线反应的谜团， 诊断为EBV+PTLD的患者维持其同种异体移植物而不返回免疫抑制。我们使用CyTOF 为了确定在没有免疫抑制的情况下从EBV+ PTLD恢复是否有利于 产生IL-10的B调节细胞的发育。总之，这些研究将提供新的机制， 深入了解对EBV的免疫反应，并将有助于改善诊断，管理和 治疗小儿移植受者的EBV疾病。

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.