Immune reconstitution to Aspergillus

针对曲霉菌的免疫重建

• 批准号: 7463673
• 负责人: Kieren A. Marr
• 金额: $ 8.21万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7463673
• 关键词: Address; Alleles; Allergic; Allergic Bronchopulmonary Aspergillosis; Allogenic; Animal Model; Antifungal Agents; Antigen-Presenting Cells; Antigens; Aspergillosis; Aspergillus; Aspergillus fumigatus; Autoantigens; Autologous; B-Lymphocytes; Biological; Blast Cell; Blood; CD4 Positive T Lymphocytes; Cell Count; Cell Proliferation; Cell secretion; Cells; Cellular Immunity; Cessation of life; Chromosomes, Human, Pair 6; Class; Complementary DNA; Complex; Cox Proportional Hazards Models; DNA Sequence; Data; Development; Engraftment; Enrollment; Environment; Epidemiology; Epitopes; Exhibits; Frequencies; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genomics; Goals; Haplotypes; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Histocompatibility Antigens Class II; Human; Hyphae; Immune; Immune response; Immunity; Immunocompromised Host; Incidence; Individual; Infection; Interferon Type II; Interleukin-4; Invasive; Kinetics; Knowledge; Libraries; Longitudinal Studies; Lung; MHC Class II Genes; Maps; Measures; Methods; Molds; Monitor; Mycoses; Natural Killer Cells; Neutropenia; Numbers; Open Reading Frames; Outcome; Outcome Measure; Patients; Pattern; Performance; Peripheral Blood Mononuclear Cell; Phenotype; Physiologic pulse; Polymerase Chain Reaction; Population; Predisposition; Preparation; Promoter Regions; Prophylactic treatment; Proteins; Pulse taking; Range; Rate; Recovery; Research Personnel; Retrospective Studies; Risk; Role; Sample Size; Sampling; Screening procedure; Staging; T-Lymphocyte; Testing; Therapeutic; Time; Transplant Recipients; Transplantation; Tumor Necrosis Factor-alpha; Vaccines; Week; attributable mortality; base; cell preparation; cytokine; day; design; fungus; healthy volunteer; human TNF protein; immune function; indexing; mortality; neutrophil; prevent; programs; reconstitution; response; trend

The annual incidence of invasive aspergillosis (IA) ranges from 10 to15% in allogeneic hematopoietic stem cell (HCT) recipients, with mortality approximating 80%; as such, this infection has become a prominent cause of infection-related death after HCT. Infection now occurs primarily late in the course of allogeneic HCT, after neutrophil engraftment. Epidemiology is consistent with the recent recognition that effective immunity in animal models requires robust CD4+ T helper type-1 (Th1) responses. However, no large studies have been performed to evaluate Aspergillus-specific immune reconstitution. We have developed the methods to measure cellular responses to Aspergillus antigens, and demonstrated reproducibly variable responses in healthy volunteers. We propose a longitudinal immune-reconstitution study to evaluate the hypothesis that CD4+ T cell reconstitution is important to protect from IA late after allogeneic HCT, with multiple factors, including donor transferred immunity, potentially impacting immune reconstitution. Specific aims will be to: 1. Determine if reconstituted cellular immunity predicts risks for, and outcomes of IA. Patients will be enrolled in a longitudinal study to evaluate whether reconstituted cell numbers (DC1, DC2, T cell subtypes, NK cells and B cells) and functional responses to A. fumigatus hyphal antigen predict risks for, and outcomes of IA. In Aim 2, studies will determine the significance of variable frequencies of reactive CD4+ T cells and cytokine patterns in healthy donors. Donor responses will be evaluated to test the hypothesis that low frequencies of IFN-gamma producing CD4+ T cells in healthy people are associated with MHC alleles, potentially including specific Class II haplotypes and/or polymorphism(s) in the Class III region (TNF-alpha gene). The impact of donor responses on recipient reconstitution will be evaluated. Studies in Aim 3 will identify Aspergillus fumigatus antigens presented to healthy human CD4+ T cells. Aspergillus-specific CD4+ T cell clones will be generated from healthy subjects by sequential stimulation with hyphal antigens. Classical HLA-restricted CD4+ clones will be used to screen pooled libraries of A. fumigatus cDNA, with sequential screens identifying individual T-cell antigens. This study will be performed with the goal of defining the mechanisms of post-transplant immune protection against Aspergillus species. This information will be valuable for development of strategies to prevent and treat fungal infections in immunocompromised peiople.

侵袭性曲霉病（IA）在异基因造血干细胞中的年发病率为10 ~ 15 细胞（HCT）受体，死亡率接近80%;因此，这种感染已成为一个突出的 HCT后感染相关死亡的原因。感染现在主要发生在同种异体移植过程的晚期。 HCT，中性粒细胞植入后。流行病学与最近认识到的有效 动物模型中的免疫需要强的CD 4 + T辅助细胞1型（Th 1）应答。然而，没有大型 已经进行了研究以评价铜绿假单胞菌特异性免疫重建。我们已经开发 测定细胞对曲霉属抗原反应的方法，并证明可重复性可变 健康志愿者的反应。我们提出了一项纵向免疫重建研究，以评估 假设CD 4 + T细胞重建对于同种异体HCT后晚期IA保护是重要的， 多种因素，包括供体转移免疫，可能影响免疫重建。具体 目标是：1.确定重建的细胞免疫是否可预测IA的风险和结局。患者 将被纳入纵向研究，以评估重建的细胞数量（DC 1，DC 2，T细胞）是否 亚型、NK细胞和B细胞）和对A.烟曲霉菌丝抗原可预测 的结果。在目标2中，研究将确定不同频率的反应性CD 4 + T细胞的意义。 细胞和细胞因子模式。将对捐助者的反应进行评价，以检验以下假设： 健康人中产生IFN-γ的CD 4 + T细胞的低频率与MHC等位基因相关， 可能包括特定的II类单倍型和/或III类区域（TNF-α）中的多态性 基因）。将评估供体反应对受体重建的影响。目标3中的研究将 鉴定呈递给健康人CD 4 + T细胞的烟曲霉抗原。巨噬细胞特异性CD 4 + T细胞克隆将通过用菌丝抗原连续刺激从健康受试者产生。 经典HLA限制性CD 4+克隆将用于筛选A.烟曲霉cDNA， 鉴定单个T细胞抗原的连续筛选。本研究的目的是确定 对曲霉菌属物种的移植后免疫保护的机制。此信息将 对免疫功能低下人群真菌感染的预防和治疗策略的制定具有重要价值。