Evaluating New Targets of CMV Cellular Immunity

评估 CMV 细胞免疫的新靶点

• 批准号: 7987158
• 负责人: John A Zaia
• 金额: $ 40.53万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7987158
• 关键词: Affect; Algorithms; Allogenic; Antiviral Agents; Antiviral Therapy; Appearance; Biological Markers; CD8-Positive T-Lymphocytes; Cell Count; Cell Transplantation; Cell physiology; Cellular Immunity; Cessation of life; Clinical; Clinical Trials; Cytomegalovirus; Cytomegalovirus Infections; DNA; Development; Disease; Dissection; Elements; Epigenetic Process; Evaluation; Event; Failure; Funding; Future; Gene Expression; Genes; Genetic; Genetic Transcription; Genotype; Grant; Hematopoietic; Hematopoietic stem cells; Immune; Immune system; Immunity; Immunophenotyping; Infection; Intervention Trial; Kinetics; Laboratories; Lead; Lectin; Ligands; Link; Lytic; Mediating; Messenger RNA; Methods; Modeling; Modification; Molecular; Mutation; Natural Killer Cells; Outcome; Patients; Persons; Phenotype; Population; Process; Production; Progress Reports; Proteins; Receptor Gene; Recovery; Relative (related person); Research; Research Design; Risk; Risk Factors; Role; Site; Stem cell transplant; T cell response; T-Lymphocyte; Testing; Time; Transplant Recipients; Transplantation; Virus; Virus Diseases; adaptive immunity; base; cohort; cytokine; immune function; immunoglobulin receptor; improved; programs; promoter; public health relevance; receptor; receptor expression; reconstitution; research clinical testing; response; therapy outcome

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.

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aKIR 2DS 2和aKIRDS 4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NKG 2）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。 公共卫生相关性：人CMV感染仍然是移植患者的重要感染，其中感染的再激活可导致重大问题。迄今为止，资助活动的重点是了解控制受体中CMV再激活的供体来源的免疫因子，并已表明涉及先天免疫系统的特定组分，即供体杀伤免疫球蛋白受体（KIR）基因型。该更新申请提出了一项临床试验，该试验基于在<1500 gc/ml CMV DNA水平下停止抗病毒治疗来测试CMV管理的先发制人策略，并将治疗需求和结果与各种NK/KIR基因型和功能相关联。结果将证实KIR基因型和表达以及HLA配体相容性是否可以用作移植后保护免受CMV的生物标志物。在分子水平上对CMV保护和失败的相关事件进行分析，将有助于更好地理解免疫力的这一重要方面，并可为如何将这些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，并且随着影响他们的风险因素信息的改善，这可能对测试新抗病毒剂的研究设计产生重要影响。