Immune control of chronic viral infection in solid organ transplantation

拯救生命的实体器官移植所需的免疫抑制诱导显著的 发病率，包括移植受者中潜伏性病毒感染复发增加。 在美国，大约60-70%的成年人是潜伏感染， 巨细胞病毒（CMV）。潜伏CMV的控制被认为依赖于一种持续活跃的 免疫反应，特别是记忆T淋巴细胞。免疫力正常的人 系统中，潜在CMV的控制是一场持续的“战斗”，并导致所谓的内存膨胀。 在老年人中，CMV应答细胞可占总CD 8 T细胞的50%以上。 细胞群尽管积极监测和抗病毒预防， 移植受者有10-15%的CMV复发率，表现为 孤立的病毒血症或可能包括终末器官损伤。为了更好地了解免疫系统 实体器官移植受者对CMV的反应，我们以前曾使用多- 参数流式细胞术，以表征移植前CMV应答性CD 8 + T细胞 到移植后一年的心脏或肾脏移植受者队列。引人注目的是， 尽管缺乏CMV再活化的临床证据，但CMV应答性CD 8 T细胞 在治疗后的第一年，CD 8细胞从约4%增加到12%。 移植初步数据表明，扩增维持了克隆竞争， 表明随时间变化的功能的克隆内异质性。这些数据使我们 免疫抑制诱导CMV寡克隆扩增的假说- 反应性T细胞导致加速膨胀和过早免疫 衰老为了解决这个假设，我们已经开始与马克·戴维斯合作， 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VA移植中心。我们将使用创新的 包括尖端细胞术和单细胞分析的方法。另外还 提出以下目标：目的1，确定是否移植和免疫抑制 诱导的扩增改变T细胞库和功能，目的2，确定是否 器官移植中的免疫抑制导致器官的过早衰老。 CMV应答人群和功能应答降低。的结果予以 这些研究将使我们对CMV反应性T细胞的生物学有新的基本认识， 可以用来开发新的治疗方法，延长退伍军人的生命。

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.