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Natural Killer Cell Receptor Diversity and CMV in Hematopoietic Cell Transplantat

造血细胞移植中的自然杀伤细胞受体多样性和巨细胞病毒

基本信息

批准号：
8474829
负责人：
Steven Aaron Pergam
金额：
$ 13.41万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-20 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8474829
关键词：
Affect Antiviral Agents Area Biometry Blood Candidate Disease Gene Cell Transplants Cells Clinical Clinical Data Clinical Research Cohort Studies Color Communicable Diseases Complication Cytomegalovirus Cytomegalovirus Infections DNA Data Databases Development Disease Donor Selection Epidemiologic Factors Evaluation FCGR3B gene Flow Cytometry Frequencies Genes Genetic Genetic Polymorphism Genotype Goals Haplotypes Hematopoietic Immune Immunity Immunobiology Immunogenetics Incidence Individual Infection Instruction KIR3DS1 Kinetics Laboratories Lead Life Lymphocyte Measures Molecular Morbidity - disease rate NCAM1 gene NK cell receptor NKB1 Natural Killer Cells Outcome Phenotype Play Pneumonia Predisposition Prevalence Prevention Prevention strategy Principal Investigator Prophylactic treatment Receptor Gene Research Research Personnel Risk Role Sampling Surface T cell response T-Lymphocyte Techniques Training Training Programs Transplant Recipients Transplant-Related Disorder Transplantation Universities Validation Viral Viral Load result Viral load measurement Virus Diseases Washington Work base career career development case control cohort computerized cytomegalovirus receptor cytotoxic design experience genetic analysis hematopoietic cell transplantation immunoprophylaxis insight killer immunoglobulin-like receptor mortality novel peripheral blood prevent prophylactic prospective receptor reconstitution research study skills skills training

项目摘要

Dr. Pergam completed an MPH degree and Infectious Diseases training at the University of Washington. This proposal describes a 5-year training program which will allow him to develop an independent academic career in clinical research studying the genetics of host immunity to cytomegalovirus (CMV) in transplant. This project will build on preliminary work evaluating the role of killer immunoglobulin-like receptors (KIR) in CMV infection in hematopoietic cell transplantation (HOT). CMV is the most common viral infection in HOT, with over 60% of seropositive recipients reactivating, and 9% developing life-threatening complications. Since natural killer (NK) cells recover quickly after transplantation, they may play an important role in the control of reactivation in the early post-transplant period. Our preliminary studies provide new evidence of an increased risk of invasive CMV disease.in recipients who receive only one donor activating KIR gene. We also show that individual donor KIR genes, particularly KIR3DS1, may decrease rates of both reactivation and invasive CMV disease. In addition, our data suggests that fewer cytotoxic CD56¿"/KIR* natural killer cells in the post-HCT period increase the risk of CMV reactivation. In our first Aim, we will evaluate the associations between KIR and CMV quantitative phenotypes using a retrospective cohort of seropositive HOT recipients (Aim 1a). We will then sequence donor KIR3DL1/DS1 as a candidate gene, and assess it for associations with CMV pneumonia using a case control approach (Aim 1b). Finally, we will prospectively evaluate post-HCT NK cell and KIR reconstitution in the laboratory and determine how they affect CMV reactivation (Aim 2). Together, these studies will provide new insights into the role of NK cells in CMV immunobiology. RELEVANCE (See instructions): CMV remains the most common viral infection in transplantation, and is associated with significant morbidity and mortality. Through these genetic studies we hope to identify better predictors for CMV reactivation and disease, which could help to alter donor selection, identify appropriate candidates for aggressive antiviral prophylaxis pre-transplant, and may eventually lead to a reduction in the burden of CMV complications in HCT.

Pergam 博士在华盛顿大学完成了公共卫生硕士学位和传染病培训。该提案描述了一个为期 5 年的培训计划，该计划将使他能够发展独立的学术能力从事临床研究，研究移植中宿主对巨细胞病毒（CMV）免疫的遗传学。该项目将建立在评估杀伤性免疫球蛋白样受体（KIR）在造血细胞移植（HOT）中的 CMV 感染。 CMV 是 HOT 中最常见的病毒感染，超过 60% 的血清阳性受者重新激活， 9% 出现危及生命的并发症。由于自然杀伤 (NK) 细胞在术后恢复很快移植后，它们可能在移植后早期的再激活控制中发挥重要作用时期。我们的初步研究提供了侵袭性巨细胞病毒疾病风险增加的新证据。仅接受一名激活 KIR 基因的捐赠者的受者。我们还表明，个体供体 KIR 基因，特别是 KIR3DS1，可能会降低再激活和侵袭性 CMV 疾病的发生率。此外，我们的数据表明，HCT 后时期细胞毒性 CD56¿"/KIR* 自然杀伤细胞的减少会增加风险 CMV 重新激活。在我们的第一个目标中，我们将评估 KIR 和 CMV 定量之间的关联使用血清阳性 HOT 接受者回顾性队列研究表型（目标 1a）。然后我们将排序供体 KIR3DL1/DS1 作为候选基因，并使用案例评估其与 CMV 肺炎的关联控制方法（目标 1b）。最后，我们将前瞻性评估 HCT 后 NK 细胞和 KIR 重建实验室并确定它们如何影响 CMV 重新激活（目标 2）。这些研究将共同提供关于 NK 细胞在 CMV 免疫生物学中的作用的新见解。相关性（参见说明）： CMV 仍然是移植中最常见的病毒感染，并且与显着的发病率相关和死亡率。通过这些基因研究，我们希望找到更好的 CMV 重新激活预测因子疾病，这可能有助于改变捐赠者的选择，确定积极抗病毒药物的合适候选者移植前进行预防，最终可能会减轻 CMV 并发症的负担血细胞CT。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Evaluation of routine pretransplantation screening for methicillin-resistant Staphylococcus aureus in hematopoietic cell transplant recipients.

DOI：
10.1016/j.ajic.2014.10.010
发表时间：
2015-01
期刊：
American journal of infection control
影响因子：
4.9
作者：
Miles-Jay A;Podczervinski S;Stednick ZJ;Pergam SA
通讯作者：
Pergam SA

Oseltamivir-resistant novel influenza A (H1N1) virus infection in two immunosuppressed patients - Seattle, Washington, 2009.

两名免疫抑制患者出现奥司他韦耐药的新型甲型流感 (H1N1) 病毒感染 - 华盛顿州西雅图，2009 年。

DOI：
发表时间：
2009
期刊：
MMWR. Morbidity and mortality weekly report
影响因子：
0
作者：
CentersforDiseaseControlandPrevention(CDC)
通讯作者：
CentersforDiseaseControlandPrevention(CDC)

Employee influenza vaccination in a large cancer center with high baseline compliance rates: comparison of carrot versus stick approaches.

具有高基线合规率的大型癌症中心的员工流感疫苗接种：胡萝卜与大棒方法的比较。

DOI：
10.1016/j.ajic.2014.11.025
发表时间：
2015
期刊：
American journal of infection control
影响因子：
4.9
作者：
Podczervinski,Sara;Stednick,Zach;Helbert,Lois;Davies,Judith;Jagels,Barbara;Gooley,Ted;Casper,Corey;Pergam,StevenA
通讯作者：
Pergam,StevenA

Cytomegalovirus pneumonia in hematopoietic stem cell recipients.