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（由申请方提供）：该提案旨在了解致病性慢病毒感染对衰老免疫系统的影响，这是一种免疫损伤的生理状态。这个问题的重要性在于它涉及一个关键的公共卫生问题， 50岁以上的HIV感染者的数量正在增加，这是由于有效的联合抗逆转录病毒疗法（cART）的显著疗效和老龄人口中新的HIV感染的发病率增加。已经充分确定，疫苗诱导的免疫应答的稳健性是阐明免疫能力水平的有力工具和研究免疫功能障碍机制的有用模型。我们对来自接受cART的HIV感染者的外周血的研究表明，对季节性流感疫苗的Ab应答随着年龄的增长而受损，并且与血液中指定为外周T滤泡辅助细胞（pTfh）的CD 4亚群的免疫活化增加和功能缺陷相关。这些细胞的一个亚群被认为在功能上类似于生发中心（GC）Tfh，其为B细胞分化成抗体产生细胞提供关键帮助，但是pTfh与GC Tfh和Tfh从血液到淋巴组织的运输的关系尚未最终确定。根据我们的研究结果，我们假设1。衰老与Tfh的功能缺陷有关，导致疫苗应答受损;尽管用cART进行了病毒学控制，但HIV感染使这些缺陷变得更糟。免疫激活加剧了Tfh功能障碍。Tfh-B细胞相互作用只能通过淋巴组织的研究来回答，这在恒河猴中是最可行的。我们的团队在淋巴结的原位分析方面具有特殊的专业知识，这将使我们能够原位研究Tfh和B细胞的相互作用。.我们将比较年轻和年老的SIV感染猕猴与控制病毒血症的反应，季节性流感和破伤风疫苗的T依赖性免疫反应，研究新的和回忆抗体反应。SIV未感染RM将作为对照。我们将通过淋巴结和外周血细胞中的表型、细胞功能和基因转录研究，对总Tfh和B细胞和抗原特异性Tfh和B细胞进行表征，研究疫苗应答受损的机制。原位免疫组织学和组织细胞学研究将为衰老和衰老并发SIV感染对胃癌中Tfh和B细胞的影响提供新的见解。我们将研究Tfh表型的细胞是否与加强疫苗接种相关地运输到LN。我们将更精确地定义潜在炎症和免疫激活在维持免疫功能障碍中的作用，并确定疫苗反应性的预测性免疫特征。将研究皮下注射白细胞介素21（标志性Tfh细胞因子）作为增强疫苗应答的方式。这些发现对HIV感染的老年人群具有相关性。