Systems Biology in Vaccination Post Autologous Hematopoietic Cell Transplant

自体造血细胞移植后疫苗接种中的系统生物学

• 批准号: 8307076
• 负责人: MIRIAM MERAD
• 金额: $ 28.1万
• 依托单位: BAYLOR RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-05 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8307076
• 关键词: Adjuvant; Age; Age-Years; Allogenic; Antibody Formation; Antigen-Presenting Cells; Antigens; Autologous; B-Lymphocytes; BLR1 gene; Biological Assay; Biological Markers; Blood; Bone Marrow Transplantation; CD4 Positive T Lymphocytes; Cell Count; Cell Transplantation; Cell Transplants; Cell physiology; Cells; Combined Vaccines; Competence; Data; Dendritic Cells; Development; Disease; Disease remission; Dose; Evolution; Frequencies; Future; Gene Expression; Generations; Goals; Helper-Inducer T-Lymphocyte; Hematopoietic; Human; Immune; Immune Cell Activation; Immune response; Immune system; Immunization; Immunocompromised Host; Immunologic Markers; Individual; Influenza; Influenza vaccination; Instruction; Kinetics; Literature; Measures; Morbidity - disease rate; Multiple Myeloma; Patients; Protocols documentation; Recruitment Activity; Regimen; SELL gene; ST14 gene; Signal Transduction; System; Systems Analysis; Systems Biology; T cell response; T-Lymphocyte; Testing; Time; Transplantation; Vaccination; Vaccines; base; design; healthy volunteer; improved; influenza virus vaccine; monocyte; mortality; novel; prevent; reconstitution; response; vaccination strategy

Influenza causes significant morbidity and mortality in hematopoietic cell transplantation (HCT) recipients, who are immunocompromised. Vaccination is the most effective way of preventing influenza but is less effective in immunocompromised patients than in healthy individuals. Thus, there is a need to understand the mechanisms underlying poor vaccine responses as well as establish biomarkers of immune competence. We surmise that understanding the relationships between antigen presenting cells (including monocytes and DCs), influenza-specific CD4+ T cells and antibody responses elicited by vaccination may enable a more rational design of vaccination strategies and timing in this group of patients. All studies to date have shown diminished CD4+ T cell numbers and proliferative T cell responses even at 12 months post transplant. We will utilize a systems biology analysis to define the immune alteration underlying the diminished responses to influenza vaccines in this group of patients. This will form a ground for development of new immuneenhancing strategies. We will focus on systems biology analysis of three cellular compartments that are essential for the generation and the quality of antibody responses to vaccines - the inducers (dendritic cells/monocytes and their subsets); regulators (T follicular helper cells - Tfh), and effectors (B cells). To date, there are no studies describing a systematic and comprehensive analysis of the reconstitution of these three blood compartments in patients who have undergone autologous HCT. Moreover, Tfh immune reconstitution after transplant (allogeneic or autologous) has not been examined for the identification of these cells until very recently. The alteration(s) in either or all of these compartments will have an impact on the quality of flu vaccine responses after HCT. Thus, our study presents an opportunity to analyze, at a systems level, the responses to flu vaccine in patients who have undergone HCT. Three aims are proposed: AIM 1: To establish the cellular and transcriptional signatures of response to flu vaccination in patients who underwent autologous HCT and in age-matched healthy volunteers. AIM 2: To establish the kinetics of blood DC subsets, Tfh and B cell compartments reconstitution in patients who underwent autologous HCT. AIM 3: To establish the functional competence of blood DC subsets and Tfh cells in patients who underwent autologous HCT.

流感在造血细胞移植（HCT）受者中引起显著的发病率和死亡率， 免疫力低下的人接种疫苗是预防流感最有效的方法，但 在免疫功能低下的患者中比在健康个体中有效。因此，有必要了解 疫苗应答差的潜在机制以及建立免疫能力的生物标志物。 我们认为，了解抗原呈递细胞（包括单核细胞和 DC）、流感特异性CD 4 + T细胞和疫苗接种引起的抗体应答可能使更多的 在这组患者中合理设计疫苗接种策略和时机。迄今为止的所有研究都表明， 即使在移植后12个月，CD 4 + T细胞数量和增殖T细胞反应也会减少。我们 将利用系统生物学分析来确定免疫改变的基础上减少反应， 流感疫苗在这类患者中的应用这将为开发新的免疫增强剂奠定基础。 战略布局我们将集中在系统生物学分析的三个细胞区室， 对于疫苗抗体应答的产生和质量至关重要-诱导剂（树突状细胞） 细胞/单核细胞及其亚群）;调节因子（T滤泡辅助细胞- Tfh）和效应因子（B细胞）。到目前为止， 没有研究描述了这三个重建的系统和全面的分析， 接受自体HCT的患者的血液隔室。此外，Tfh免疫重建 移植后（同种异体或自体）尚未检查这些细胞的鉴定， 就在最近这些部分中的任何一个或所有部分的改变都会对流感的质量产生影响。 HCT后的疫苗应答。因此，我们的研究提供了一个机会，在系统层面上分析， 接受过HCT的患者对流感疫苗的反应。提出了三个目标： 目的1：在以下患者中建立流感疫苗接种反应的细胞和转录特征： 在年龄匹配的健康志愿者中进行自体HCT。 目的2：建立慢性乙型肝炎患者外周血DC亚群、Tfh和B细胞亚群重建的动力学 接受了自体血细胞比容检查 目的3：建立外周血DC亚群和Tfh细胞的功能能力， 自体红细胞压积