Evaluating New Targets of CMV Cellular Immunity

描述（由申请人提供）：这是一份续期申请，建议将第一个资助期的发现延长到基于个体化巨细胞病毒危险因素的治疗算法的抗病毒管理和相关研究的临床试验。该模型利用造血细胞移植（HCT）受者巨细胞病毒高活化率来研究在有或没有这种活化的受者中控制这种事件的先天和适应性免疫因子。迄今为止的研究表明，控制巨细胞病毒再激活的是先天免疫系统，而不是适应性免疫系统。具体来说，供体基因型中激活KIR （aKIR）基因aKIR2DS2和aKIRDS4的存在高度预测了受体最终控制未来CMV感染的程度。在具有“保护性”供体aKIR基因型的人群中，已知的失败率为解剖影响NK控制这种特定病毒感染的分子因素提供了模型。相反，其他NK受体的保护作用，如NKG2，将在没有CMV再激活的患者中寻找。本研究的假设是先天反应控制巨细胞病毒的再激活，当它们失败时，是由于遗传或NK受体基因表达的改变。有两个目的：1)继续对HCT受者CMV模型进行临床免疫学研究，利用CMV危险因素指导先发制人的抗病毒治疗；2)实验室评估自然杀伤（NK）细胞的免疫表型和功能，重点是表征aKIR基因的mRNA水平和定义启动子序列。评估NK细胞在hct后不同时间的外观和功能将与病毒学事件相关。这可能会导致hct后患者管理的更好方法，并且更好地了解KIR和基于凝集素的NK受体的作用，以及与它们沉默相关的因素，将推进免疫的这一重要方面。

DESCRIPTION (provided by applicant): This is a renewal application which proposes to extend the finding of the first funding period to a clinical test of antiviral management and correlative research using a treatment algorithm based on individualized CMV risk factors. The model uses the high rate of CMV reactivation in recipients of hematopoietic cell transplantation (HCT) to study the innate and adaptive immune factors which govern this event in those with and without such reactivation. The study to date has demonstrated that it is the innate immune system rather than the adaptive immune system which controls CMV reactivation. Specifically, the presence in the donor genotype of activating KIR (aKIR) genes, aKIR2DS2 and aKIRDS4, are highly predictive of how well the recipient will ultimately control future CMV infection. A known failure rate in persons who otherwise have a "protective" donor aKIR genotype offers a model for dissection of molecular factors which affect NK control of this specific virus infection. Conversely, the protective role of other NK receptors, such as NKG2, will be sought in patients without CMV reactivation. The hypothesis of this study is that the innate responses control CMV reactivation and when they fail, it is due to alterations in genetics or in expression of NK receptor genes. There are two aims 1) continuation of the clinical immunological study of the CMV Model in HCT recipients managed using CMV risk factors to guide preemptive antiviral therapy, and 2) the laboratory assessment of natural killer (NK) cell immunophenotypes and functions, with emphasis on characterization of mRNA levels of aKIR genes and definition of promoter sequences. Assessment of the appearance and function of NK cells at various times post-HCT will be made relative to virologic events. This could lead to a better method for patient management post-HCT, and a better understanding of the role of KIR and lectin-based NK receptors, and factors associated with their silencing, will advance this important aspect of immunity. PUBLIC HEALTH RELEVANCE: Human CMV infection remains an important infection in transplantation patients, in which reactivation of infection can lead to significant problems. To date, the grant activity has focused on understanding the donor- derived immune factors that control CMV reactivation in the recipient and has shown that specific components of the innate immune system, namely donor Killer Immunoglobulin Receptor (KIR) genotype, are involved. This renewal application proposes a clinical trial testing a preemptive strategy for CMV management based on withholding antiviral therapy at <1500 gc/ml CMV DNA levels, and will correlate need for therapy and outcome with various NK/KIR genotype and functions. The results will confirm whether KIR genotype and expression, and HLA ligand compatibility, can be used as biomarkers for protection from CMV after transplantation. Analysis of the related events at a molecular level, for both CMV protection and failure, will provide improved understanding of this important aspect of immunity, and it could provide guidance on how such information can be applied to patient management. Ultimately, this study could impact the way that transplant patients are treated, and with improved information on the risk factors affecting them, this could have important implications for the design of studies testing new antiviral agents.