MCMV infection, latency and reactivation in transplantation tolerance

项目3 项目总结 在器官捐赠者和器官接受者中CMV血清阳性的高流行率使CMV重新激活 移植后是发病率和死亡率的重要原因，也是造成移植结果不佳的原因之一。 巨细胞病毒重新激活的一个新概念指出，移植引起的炎症是早期触发 CMV转录重新激活。免疫抑制剂的应用进一步抑制病毒特异性 免疫，导致最终完成裂解病毒复制。我们假设实现强健的 供者特定的移植耐受将抑制移植相关的炎症，因此消除了一个关键的 早期触发CMV病毒基因组的表观遗传重新编程和转录重新激活，以及 从而防止CMV重新激活。我们建议以一种前瞻性的、高度的 临床相关的供者特异性移植耐受模型采用移植前供者“阴性”策略 用化学交联剂1-乙基-3-(3-二甲氨基丙基)处理的供体细胞接种疫苗 碳二亚胺(ECDI)。我们对小鼠移植耐受模型的研究已经导致了正在进行的 异体和异种移植的非人灵长类动物模型的临床前研究。此外，一个 基于相同原理首次在人类临床试验中使用多肽偶联自体细胞治疗慢性阻塞性肺疾病 多发性硬化症最近证实了这种新型耐受性的临床可行性、耐受性和安全性。 策略。我们使用MCMV的初步数据表明，这种方法阻止了耐受性 潜伏的MCMV的即刻早期(IE)基因转录重新激活。相反，急性MCMV感染 尝试耐受性诱导受损，已建立的耐受性不稳定。因此，在当前 应用程序(项目3)，我们建议使用小鼠移植模型检查以下三个领域 MCMV感染与ECDI-供体细胞耐受策略：(1)供体特异性耐受对MCMV的影响 急性感染、潜伏期的建立和潜伏期的重新激活；(2)MCMV感染对 供体特异性耐受的诱导和稳定性；(3)相互作用的细胞机制 巨细胞病毒感染与供者特异性耐受之间的相互作用。我们的长期目标是确定 在建立和维持稳定的供体特异性的同时预防巨细胞病毒再激活的治疗目标 移植耐受性。

Project 3 PROJECT SUMMARY A high prevalence of CMV seropositivity in both organ donors and organ recipients makes CMV reactivation following transplantation a significant cause for morbidity and mortality and a contributor to poor graft outcome. An emerging concept in CMV reactivation points to transplant-induced inflammation as an early trigger for CMV transcriptional reactivation. Administration of immunosuppressants further suppresses viral-specific immunity, leading to the eventual completion of lytic viral replication. We hypothesize that achieving robust donor-specific transplant tolerance will inhibit transplant-associated inflammation, therefore remove a critical early trigger for epigenetic reprogramming and transcriptional reactivation of the CMV viral genome, and consequently prevent CMV reactivation. We propose to test this hypothesis in a forward-thinking, highly clinically relevant donor-specific transplant tolerance model using a strategy of pre-transplant donor “negative vaccination” by delivery of donor cells treated with the chemical crosslinker 1-ethyl-3-(3-dimethylaminopropyl)- carbodiimide (ECDI). Our studies in murine models of transplantation tolerance have already led to ongoing pre-clinical studies in non-human primate models of allogeneic and xenogeneic transplantation. Moreover, a first-in-human clinical trial based on the same principle using peptide-coupled autologous cells in patients with multiple sclerosis recently established the clinical feasibility, tolerability, and safety of this novel tolerance strategy. Our preliminary data using MCMV demonstrated that tolerance by this approach prevented immediate early (IE) gene transcriptional reactivation from latent MCMV. Conversely, acute MCMV infection impaired attempted tolerance induction and destabilized established tolerance. Therefore, in the current application (Project 3), we propose to examine the following three areas using murine transplant models with MCMV infection and ECDI-donor cell tolerance strategy: (1) the effects of donor-specific tolerance on MCMV acute infection, establishment of latency, and reactivation from latency; (2) the effects of MCMV infection on the induction and stability of donor-specific tolerance; (3) the cellular mechanisms underlying the reciprocal interactions between MCMV infection and donor-specific tolerance. Our long-term goal is to determine therapeutic targets for prevention of CMV reactivation while establishing and maintaining stable donor-specific transplant tolerance.