Evaluating New Targets of CMV Cellular Immunity

评估 CMV 细胞免疫的新靶点

• 批准号: 8265719
• 负责人: John A Zaia
• 金额: $ 39.31万
• 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/8265719
• 关键词: Affect; Algorithms; Allogenic; Antiviral Agents; Antiviral Therapy; Appearance; Biological Markers; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Count; 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 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; 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; hematopoietic cell transplantation; 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）：这是一份续展申请，拟将第一个资助期的发现扩展到使用基于个体化CMV风险因素的治疗算法进行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) 受者体内巨细胞病毒 (CMV) 的高再激活率来研究在有或没有这种再激活的患者中控制这一事件的先天性和适应性免疫因素。迄今为止的研究表明，控制 CMV 重新激活的是先天免疫系统，而不是适应性免疫系统。具体来说，供体基因型中是否存在激活 KIR (aKIR) 基因 aKIR2DS2 和 aKIRDS4，可以高度预测受体最终控制未来 CMV 感染的程度。已知具有“保护性”供体 aKIR 基因型的人的失败率提供了一个模型，用于剖析影响 NK 对这种特定病毒感染的控制的分子因素。相反，其他 NK 受体（例如 NKG2）的保护作用将在没有 CMV 重新激活的患者中寻求。这项研究的假设是先天反应控制 CMV 重新激活，当它们失败时，这是由于遗传学或 NK 受体基因表达的改变。有两个目标：1) 继续对使用 CMV 危险因素管理的 HCT 受者进行 CMV 模型的临床免疫学研究，以指导先发性抗病毒治疗；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。将根据病毒学事件对 HCT 后不同时间的 NK 细胞的外观和功能进行评估。这可能会带来更好的 HCT 后患者管理方法，更好地了解 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：人类 CMV 感染仍然是移植患者的重要感染，感染的重新激活可能导致严重问题。迄今为止，资助活动的重点是了解控制受者体内 CMV 再激活的供体来源的免疫因子，并表明先天免疫系统的特定组成部分，即供体杀伤性免疫球蛋白受体 (KIR) 基因型，参与其中。该更新申请提出了一项临床试验，测试基于在 <1500 gc/ml CMV DNA 水平下暂停抗病毒治疗的 CMV 管理先发性策略，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免受 CMV 感染的生物标志物。在分子水平上分析 CMV 保护和失败的相关事件，将有助于更好地理解免疫的这一重要方面，并且可以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，并且随着影响移植患者的风险因素的信息得到改进，这可能对测试新抗病毒药物的研究设计产生重要影响。