Evaluating New Targets of CMV Cellular Immunity

描述(由申请人提供)：这是一份续签申请，建议将第一个资助期的发现扩展到使用基于个性化CMV风险因素的治疗算法的抗病毒管理和相关研究的临床测试。该模型利用造血细胞移植(HCT)受者巨细胞病毒(CMV)重新激活的高比率来研究在有和没有这种重新激活的受者中控制这一事件的先天和获得性免疫因素。迄今为止的研究表明，控制CMV重新激活的是先天性免疫系统，而不是获得性免疫系统。具体地说，在供体中存在激活KIR(Akir)基因的aKIR2DS2和aKIRDS4，可以高度预测接受者最终将如何很好地控制未来的CMV感染。一个已知的失败率，在那些拥有“保护性”捐献者akir基因的人中，为剖析影响NK控制这种特定病毒感染的分子因素提供了一个模型。相反，在没有CMV重新激活的患者中，将寻求其他NK受体的保护作用，如NKG2。这项研究的假设是，先天性反应控制着CMV的重新激活，当它们失败时，是由于遗传或NK受体基因表达的改变。目的有两个：1)继续巨细胞病毒模型在HCT受者中的临床免疫学研究，使用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水平和确定启动子序列。将根据病毒学事件评估HCT后不同时间NK细胞的外观和功能。这可能导致一种更好的HCT后患者管理方法，更好地理解KIR和基于凝集素的NK受体的作用，以及与其沉默相关的因素，将促进这一重要方面的免疫。 公共卫生相关性：人类巨细胞病毒感染仍然是移植患者的一种重要感染，在这种情况下，感染的重新激活可能会导致重大问题。到目前为止，赠款活动的重点是了解控制受者CMV重新激活的供者来源的免疫因素，并表明参与了先天性免疫系统的特定组成部分，即供者杀伤免疫球蛋白受体(KIR)基因。这一更新申请提出了一种临床试验，测试基于在1500 GC/ml CMV DNA水平上保留抗病毒治疗的CMV管理的先发制人策略，并将治疗需求和结果与不同的NK/KIR基因和功能相关联。这一结果将证实KIR基因和表达，以及人类白细胞抗原配基的相容，是否可以作为移植后预防CMV的生物标志物。在分子水平上分析相关事件，无论是CMV保护还是失败，都将提供对免疫这一重要方面的更好理解，并可能为如何将此类信息应用于患者管理提供指导。最终，这项研究可能会影响移植患者的治疗方式，随着影响他们的风险因素信息的改进，这可能会对测试新抗病毒药物的研究设计产生重要影响。

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.