Antibody Responses in Aging SIV Infected Monkeys

感染 SIV 的衰老猴子的抗体反应

• 批准号: 9120783
• 负责人: Savita Pahwa
• 金额: $ 81.46万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-05 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9120783
• 关键词: AIDS/HIV problem; Address; Age; Aging; Antibodies; Antibody Formation; Antibody Response; Antibody-Producing Cells; Antigens; Autologous; B-Lymphocytes; Bacterial Pneumonia; Biological Assay; Biological Markers; Blood; Bolus Infusion; CD4 Positive T Lymphocytes; Cell Communication; Cell physiology; Cells; Centers for Disease Control and Prevention (U.S.); Chickenpox; Coculture Techniques; Competence; Confocal Microscopy; Cytometry; DNA; Defect; Development; Diphtheria; Disease; Elderly; Frequencies; Functional disorder; Generations; Genetic Transcription; HIV; HIV Infections; Health; Helper-Inducer T-Lymphocyte; Histology; Human; Immune; Immune System Diseases; Immune response; Immune system; Immunity; Immunization; Immunoglobulin G; Impairment; In Situ; Incidence; Infection; Inflammation; Influenza; Influenza vaccination; Injection of therapeutic agent; Intervention; Investigation; Knowledge; Lentivirus Infections; Light; Lymphocyte Subset; Lymphoid; Lymphoid Tissue; Macaca; Macaca mulatta; Measures; Modality; Modeling; Molecular; Monkeys; Mucous Membrane; Participant; Pathogenesis; Patients; Peripheral; Persons; Pertussis; Phenotype; Physiological; Pilot Projects; Plasma; Plasmablast; Pneumococcal Infections; Pneumococcal vaccine; Public Health; RNA; Reaction; Research; Risk; Role; SIV; Secondary Immunization; Serum; Serum Markers; Site; Sorting - Cell Movement; Structure of germinal center of lymph node; Subcutaneous Injections; Suspension substance; Suspensions; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Tetanus; Tetanus Vaccine; Tissues; Vaccines; Viremia; age effect; aging population; antiretroviral therapy; base; booster vaccine; cell type; clinical practice; cytokine; demographics; differentiated B cell; immune activation; improved; influenza virus vaccine; insight; interleukin-21; lymph nodes; novel; peripheral blood; response; seasonal influenza; stem; tool; trafficking; vaccine response

 DESCRIPTION (provided by applicant): This proposal aims to understand the impact of a pathogenic lentivirus infection on the immune system in aging, a physiologic state of immune impairment. This question is significant in that it addresses a critical public health issue, given that numbers of people with HIV over age 50 is on the rise due to both, dramatic efficacy of potent combination antiretroviral therapy (cART) and increasing incidence of new HIV infections in the aging population, It is well established that robustness of vaccine -induced immune responses are a powerful tool for elucidating level of immune competence and a useful model for investigating mechanisms of immune dysfunction. Our studies with peripheral blood from HIV infected people on cART have indicated that Ab responses to seasonal influenza vaccine are impaired with aging and are associated with increased immune activation and defective function of a CD4 subset designated as peripheral T follicular helper cells (pTfh) jn blood. A subset of these cells are believed to be functionally similar to germinal center (GC) Tfh that provide critical help to B cells for differentiating into antibody producing cells, but the relatioship of pTfh to GC Tfh and Tfh traffic from blood to lymphoid tissue has not been conclusively established. Based on our findings we hypothesize that 1. Aging is associated with functional deficiency of Tfh that leads to impaired vaccine responses and 2. These defects are made worse by HIV infection despite virologic control with cART and 3. Immune activation exacerbates Tfh dysfunction. The Tfh-B cell interaction can only be answered through study of lymphoid tissue which is most feasible in rhesus macaques. Our team has special expertise in in situ analyses of lymph nodes that will enable us to investigate Tfh and B cell interaction in situ. . We will compare young and old SIV infected macaques with controlled viremia for their responses to seasonal influenza and tetanus vaccines for T-dependent immune responses to study neo and recall antibody responses. SIV uninfected RM will serve as controls. We will investigate the mechanisms of impaired vaccine responses by characterization of total and antigen-specific Tfh and B cells by phenotype, cellular function and gene transcription studies in cells from lymph nodes and peripheral blood. In situ immunohistology and histo- cytometry studies will provide novel insights into the impact of aging and that of aging complicated by SIV infection on Tfh and B cells in GC. We will study if cells with Tfh phenotype traffic to LN in association with booster vaccination. We will define more precisely the role of underlying inflammation and immune activation in perpetuating immune dysfunction and identify predictive immune signatures of vaccine responsiveness. Subcutaneous injections of interleukin 21 (the signature Tfh cytokine) will be investigated as a modality to augment vaccine responses. These findings have relevance for HIV infected aging population.

 描述（由申请人提供）：该提案旨在了解致病性慢病毒感染对衰老（一种免疫损伤的生理状态）中的免疫系统的影响，因为它解决了一个关键的公共卫生问题。 由于有效的联合抗逆转录病毒疗法 (cART) 的显着疗效以及老龄化人口中新发艾滋病毒感染发生率的增加，50 岁以上艾滋病毒感染者人数正在增加，众所周知，疫苗诱导免疫的稳健性抗体反应是阐明免疫能力水平的有力工具，也是研究免疫功能障碍机制的有用模型。我们对 HIV 感染者的外周血进行的 cART 研究表明，抗体对季节性流感疫苗的反应会随着年龄的增长而减弱，并且与衰老相关。增加免疫激活和血液中被称为外周滤泡辅助 T 细胞 (pTfh) 的 CD4 亚群的功能缺陷被认为与生发中心 (GC) Tfh 功能相似，为 B 细胞分化为抗体产生细胞提供重要帮助。 ，但 pTfh 与 GC Tfh 和 Tfh 从血液到淋巴组织的运输之间的关系尚未最终确定。根据我们的发现，我们认为 1. 衰老与功能相关。 Tfh 缺乏会导致疫苗反应受损；2. 尽管使用 cART 进行病毒学控制，但 HIV 感染会使这些缺陷变得更严重；3. 免疫加剧激活 Tfh 功能障碍只能通过淋巴组织研究来回答。在恒河猴中最可行。我们的团队在淋巴结原位分析方面拥有特殊的专业知识，这将使我们能够在原位研究 Tfh 和 B 细胞的相互作用。具有受控病毒血症的猕猴对季节性流感和破伤风疫苗的 T 依赖性免疫反应，以研究 Neo 和回忆 SIV 未感染的 RM 将作为对照，通过表征总和抗原来研究疫苗反应受损的机制。 - 通过对淋巴结和外周血细胞进行表型、细胞功能和基因转录研究来确定 Tfh 和 B 细胞的特异性，原位免疫组织学和组织细胞计数研究将为衰老的影响以及衰老所带来的复杂影响提供新的见解。 SIV 对 GC 中 Tfh 和 B 细胞的感染我们将研究具有 Tfh 表型的细胞是否与加强疫苗接种相关。皮下注射白细胞介素 21（标志性 Tfh 细胞因子）将作为增强疫苗反应的一种方式进行研究。这些发现与感染艾滋病毒的老龄化人群相关。