Immune control of chronic viral infection in solid organ transplantation

实体器官移植中慢性病毒感染的免疫控制

• 批准号: 10059137
• 负责人: JONATHAN S MALTZMAN
• 金额: --
• 依托单位: VETERANS ADMIN PALO ALTO HEALTH CARE SYS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10059137
• 关键词: Address; Adult; Age; Antiviral Agents; Biology; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell physiology; Cell surface; Cells; Cessation of life; Chronic; Clinical; Clonal Expansion; Collaborations; Cytomegalovirus; Cytometry; Data; Elderly; End stage renal failure; Epigenetic Process; Excision; Flow Cytometry; Goals; Heart Diseases; Heart Transplantation; Heterogeneity; Human; Immune; Immune response; Immune system; Immunocompetent; Immunologic Markers; Immunosuppression; Incidence; Individual; Inflammation; Kidney Transplantation; Latent virus infection phase; Lead; Life; Link; Liver; Longitudinal Studies; Lung diseases; Memory; Monitor; Morbidity - disease rate; Opportunistic Infections; Organ; Organ Transplantation; Patients; Pharmaceutical Preparations; Phenotype; Population; Population Decreases; Premature aging syndrome; Prophylactic treatment; Recurrence; Sampling; Savings; Solid; T memory cell; T-Lymphocyte; T-cell receptor repertoire; Time; Transplant Recipients; Transplantation; United States; Universities; Veterans; Viremia; Virus; Virus Diseases; Withdrawal; age associated immune deficiency; aged; cohort; design; immunosenescence; immunosuppressed; improved; innovation; insight; memory process; mortality; novel therapeutics; post-transplant; premature; prophylactic; recruit; response; senescence; single cell analysis; transplant centers

Immunosuppression required for lifesaving solid organ transplantation induces significant morbidity including increased recurrence of latent viral infection in transplant recipients. Approximately 60-70% of adults in the United States are latently infected with Cytomegalovirus (CMV). Control of latent CMV is thought to depend on a constantly active immune response, specifically by memory T lymphocytes. In those with a normal immune system, control of latent CMV is a constant “battle” and results in so called memory inflation. In aged individuals, CMV responsive cells may constitute upward of 50% of the total CD8 T cell population. Despite active monitoring and anti-viral prophylaxis, immunosuppressed transplant recipients have a 10-15% incidence of recurrent CMV manifesting either as isolated viremia or may include end-organ damage. To better understand the immune response to CMV in solid organ transplant recipients, we have previously used multi- parameter flow cytometry to characterize CMV-responsive CD8+ T cells from pre-transplant to one year post transplant in a cohort of heart or kidney transplant recipients. Strikingly, despite a lack of clinical evidence for CMV reactivation, CMV-responsive CD8 T cells increased from approximately 4% to 12% of the CD8 repertoire during the first year post- transplant. Preliminary data indicates that the expansion maintains clonal competition and suggests intraclonal heterogeneity of function that changes with time. These data lead us to the hypothesis that immunosuppression induces oligoclonal expansion of CMV- responsive T cells resulting in accelerated inflation and premature immune senescence. To address this hypothesis, we have initiated collaborations with Mark Davis, Jorg Goronzy and Purvesh Khatri at Stanford University. Subjects will be recruited from the Portland, Nashville, Pittsburgh and Palo Alto VA transplant centers. We will use innovative approaches involving cutting edge cytometry and single cell analysis . Specifically we propose the following aims: Aim1, Determine if transplantation and immunosuppression induced expansion alters the T cell repertoire and function and Aim 2, Determine if immunosuppression in the setting of organ transplantation leads to pre-mature aging of the CMV-responsive population and decreased functional responses. The results of these studies will give us new fundamental insight into the biology of CMV-responsive T cells and can be used to develop new therapies that will extend the lives of veterans.

救命的实体器官移植所需的免疫抑制导致显著 发病率，包括移植受者潜伏病毒感染复发的增加。 美国大约60%-70%的成年人潜伏感染 巨细胞病毒(CMV)。潜伏的CMV的控制被认为依赖于持续的活跃 免疫反应，特别是记忆T淋巴细胞。在免疫力正常的人中 系统中，控制潜伏的CMV是一场持续不断的“战斗”，并导致所谓的内存膨胀。 在老年人中，巨细胞病毒应答细胞可能占CD8T细胞总数的50%以上 细胞数量。尽管进行了积极的监测和抗病毒预防，但免疫抑制 移植受者有10-15%的CMV复发发生率，表现为 孤立性病毒血症或可能包括终末器官损害。为了更好地了解免疫力 在实体器官移植受者中对CMV的反应，我们以前曾使用过多个 参数流式细胞术检测移植前巨细胞病毒应答的CD8+T细胞 在心脏或肾脏移植受者队列中移植后一年。令人惊讶的是， 尽管缺乏CMV重新激活的临床证据，但CMV应答的CD8 T细胞 在CD8曲目的第一年，从大约4%增加到12%- 移植。初步数据表明，扩张保持了克隆竞争和 提示功能随时间变化的克隆内异质性。这些数据让我们了解到 免疫抑制诱导巨细胞病毒寡克隆扩增的假说 反应性T细胞导致加速充气和过早免疫 衰老。为了解决这个假设，我们发起了与马克·戴维斯的合作， 斯坦福大学的Jorg Goronzy和Purvesh Khatri。受试者将从 波特兰、纳什维尔、匹兹堡和帕洛阿尔托退伍军人管理局移植中心。我们将使用创新的 涉及尖端细胞术和单细胞分析的方法。具体来说，我们 提出以下目标：Aim1，确定移植和免疫抑制 诱导扩增改变T细胞的谱系和功能以及目标2，确定是否 器官移植过程中的免疫抑制会导致器官的早衰 对CMV有反应的人群和功能反应减少。这些研究的结果 研究将使我们对CMV反应的T细胞和 可以用来开发新的疗法，延长退伍军人的生命。