Fc Receptor Signaling in Vaccine Design for the Elderly

老年人疫苗设计中的 Fc 受体信号转导

• 批准号: 7070016
• 负责人: Biao Zheng
• 金额: $ 36.62万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7070016
• 关键词: age difference; animal old age; antibody receptor; antigen antibody reaction; antigen presentation; biological signal transduction; biotechnology; cell mediated lymphocytolysis test; cellular immunity; dendritic cells; drug quality /standard; enzyme linked immunosorbent assay; flow cytometry; humoral immunity; immune complex; immune response; immunodeficiency; immunoregulation; influenza vaccines; laboratory mouse; nonhuman therapy evaluation; small interfering RNA; vaccine development; vaccine evaluation

DESCRIPTION (provided by applicant): In the elderly, there is a significant decline in both cellular and humoral immunity, leading to a state of dysregulated immune functions, or immunosenescence. Immunosenescence compromises protection against infectious diseases and contributes to the increased susceptibility of the elderly to infection. Furthermore, immunosenescence is responsible for the diminished responsiveness of the elderly to vaccination. Thus, the elderly are particularly vulnerable and are at greater risk in the event of a bioterror attack. An impaired response to influenza virus infection and vaccination in the elderly may be clinically most relevant. The responses to influenza vaccination are significantly impaired in aged people. Both primary and secondary antibody responses to influenza vaccination are diminished in the elderly. Even when the antigenic match between influenza vaccine and circulating virus is close, vaccination provides protection for only 30%- 40% of subjects aged >= 65 years, compared with 70-90% of those aged < 65 years. The currently available trivalent inactivated influenza vaccines are particularly ineffective in preventing deaths among elderly persons with associated chronic conditions, underscoring the need for influenza vaccines that are more effective in elderly persons who need them most. Fc receptors (FcR) link the humoral and cellular branches of the immune system and have crucial functions in the activation and modulation of immune responses. Our recent studies indicate that immunization with immune complexes (IC) can correct the age-related deficiency in humoral and cellular immune responses to model antigens as well as influenza vaccines in mice. We have also demonstrated that the inhibitory Fc receptor, Fcgamma IIB, can be selectively ablated by RNA interference using small interfering RNA (siRNA). Thus, manipulating FcR signaling and vaccination with IC may constitute a novel immunization strategy to provide effective protection to immune compromised elderly population against influenza infection. In this project, we propose the following specific aims: Aim 1. Determine the mechanisms by which immune responses are regulated by IC Aim 2. Study the modulation of immune responses by selective signaling Fc receptors Aim 3. Determine the effectiveness of 1C vaccines in overcoming age-related immune deficiency.

描述（由申请人提供）：在老年人中，细胞和体液免疫都显着下降，导致免疫功能失调或免疫衰老状态。免疫衰老会损害对传染病的保护，并导致老年人感染的易感性增加。此外，免疫衰老负责老年人对疫苗接种的反应性降低。因此，老年人特别容易受到伤害，并且在发生生物侵袭的情况下，面临更大的风险。对老年人的流感病毒感染和疫苗接种的反应受损可能是临床上最相关的。老年人对流感疫苗接种的反应严重受损。老年人对流感疫苗接种的原发性和继发性抗体反应都会减少。即使流感疫苗和循环病毒之间的抗原匹配接近，疫苗接种也只能以30％至40％的年龄> = 65岁的受试者提供保护，而年龄<65岁的人中有70-90％。当前可用的三价灭活流感疫苗在预防具有相关慢性病的老年人的死亡方面尤为无效，强调了对最需要他们最有效的老年人更有效的流感疫苗的需求。 FC受体（FCR）连接免疫系统的体液和细胞分支，并在免疫反应的激活和调节中具有至关重要的功能。我们最近的研究表明，免疫复合物（IC）的免疫可以纠正小鼠对模型抗原以及流感疫苗的体液和细胞免疫反应的年龄缺乏。我们还证明，使用小的干扰RNA（siRNA）可以通过RNA干扰选择性地烧蚀抑制性FC受体FCGAMMA IIB。因此，通过IC操纵FCR信号传导和疫苗接种可能构成一种新型的免疫策略，可以为免疫受损的老年人群体提供有效的保护，以防止流感感染。在这个项目中，我们提出以下具体目的： 目标1。确定免疫反应受到IC调节的机制 AIM 2。通过选择性信号FC受体研究免疫反应的调节 目标3。确定1C疫苗在克服年龄相关的免疫缺陷中的有效性。