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

• 批准号: 8100193
• 负责人: Steven Aaron Pergam
• 金额: $ 13.46万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 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/8100193
• 关键词: Affect; Antiviral Agents; Area; Biometry; Blood; Candidate Disease Gene; Cell Transplantation; 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; abstracting; base; career; career development; case control; cohort; computerized; cytomegalovirus receptor; cytotoxic; design; experience; genetic analysis; immunoprophylaxis; insight; killer immunoglobulin-like receptor; mortality; novel; peripheral blood; prevent; prophylactic; prospective; receptor; reconstitution; research study; skills; skills training

DESCRIPTION (provided by applicant): 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¿(tm)/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. (End of Abstract)

简介（由申请人提供）：Dr. Pergam在华盛顿大学完成了公共卫生硕士学位和传染病培训。该建议描述了一个为期5年的培训计划，这将使他能够在移植中研究巨细胞病毒（CMV）宿主免疫遗传学的临床研究中发展独立的学术生涯。该项目将建立在初步评估杀伤免疫球蛋白样受体（KIR）在造血细胞移植（HOT）中巨细胞病毒感染中的作用的基础上。巨细胞病毒是HOT中最常见的病毒感染，超过60%的血清阳性受体重新激活，9%发生危及生命的并发症。由于自然杀伤（NK）细胞在移植后恢复迅速，它们可能在移植后早期的再激活控制中起重要作用。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。在只接受一个供体激活KIR基因的受者中。我们还表明，个体供体KIR基因，特别是KIR3DS1，可能降低再激活率和侵袭性巨细胞病毒疾病。此外，我们的数据表明，hct后时期细胞毒性CD56¿(tm)/KIR*自然杀伤细胞的减少增加了CMV再激活的风险。在我们的第一个目标中，我们将使用血清阳性HOT受体的回顾性队列（Aim 1a）来评估KIR和CMV定量表型之间的关系。然后，我们将对供体KIR3DL1/DS1作为候选基因进行测序，并使用病例对照方法评估其与巨细胞病毒肺炎的相关性（Aim 1b）。最后，我们将在实验室中前瞻性地评估hct后NK细胞和KIR重构，并确定它们如何影响巨细胞病毒的再激活（目的2）。总之，这些研究将为NK细胞在巨细胞病毒免疫生物学中的作用提供新的见解。相关性（见说明书）：巨细胞病毒仍然是移植中最常见的病毒感染，并与显著的发病率和死亡率相关。通过这些基因研究，我们希望找到CMV再激活和疾病的更好的预测因子，这可能有助于改变供体选择，确定移植前积极抗病毒预防的合适候选人，并可能最终导致减少HCT中CMV并发症的负担。（摘要结束）