Evaluating New Targets of CMV Cellular Immunity

描述（由申请人提供）：这是一项延续申请，建议将第一个资助期的发现扩展到抗病毒管理的临床试验和相关研究，使用基于个体化CMV风险因素的治疗算法。该模型使用造血细胞移植（HCT）受体中CMV再激活的高比率来研究在有和没有这种再激活的情况下控制该事件的先天性和适应性免疫因素。迄今为止的研究表明，是先天免疫系统而不是适应性免疫系统控制CMV再激活。具体而言，供体基因型中激活KIR（aKIR）基因aKIR2DS2和aKIRDS4的存在高度预测受体最终控制未来CMV感染的程度。在具有“保护性”供体aKIR基因型的人中已知的失败率提供了一个模型，用于解剖影响NK控制这种特定病毒感染的分子因素。相反，在没有CMV再激活的患者中，将寻求其他NK受体（如NKG2）的保护作用。本研究的假设是先天性反应控制CMV再激活，当它们失败时，这是由于遗传学或NK受体基因表达的改变。有两个目的：1）继续使用CMV风险因素管理的HCT接受者中CMV模型的临床免疫学研究，以指导先发制人的抗病毒治疗，以及2）自然杀伤（NK）细胞免疫表型和功能的实验室评估，重点是aKIR基因mRNA水平的表征和启动子序列的定义。将相对于病毒学事件评估HCT后不同时间NK细胞的外观和功能。这可能导致更好的方法用于HCT后的患者管理，并且更好地理解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.