Fc Receptor Signaling in Vaccine Design for the Elderly

描述(申请人提供)：在老年人中，细胞免疫和体液免疫都显著下降，导致免疫功能失调，或免疫衰老。免疫衰老损害了对传染病的保护，并增加了老年人对感染的易感性。此外，免疫衰老是老年人对疫苗接种反应减弱的原因。因此，老年人特别脆弱，如果发生生物恐怖袭击，他们面临的风险更大。老年人对流感病毒感染和接种疫苗的反应受损可能是临床上最相关的。老年人对流感疫苗的反应明显受损。老年人对流感疫苗的一次和二次抗体反应均减弱。即使流感疫苗和流行病毒的抗原匹配很接近，接种疫苗也只为65岁的受试者提供了30%-40%的保护，而65岁的受试者的这一比例为70%-90%。目前可用的三价灭活流感疫苗在预防患有相关慢性病的老年人死亡方面尤其无效，这突显了需要对最需要的老年人更有效的流感疫苗。 Fc受体(FCR)连接免疫系统的体液和细胞分支，在免疫反应的激活和调节中起着至关重要的作用。我们最近的研究表明，免疫复合体(IC)免疫可以纠正小鼠对模型抗原和流感疫苗的体液和细胞免疫反应的年龄相关缺陷。我们还证明了抑制Fc受体FcGamma IIB可以通过使用小干扰RNA(SiRNA)的RNA干扰选择性地被消融。因此，操控FCR信号和IC疫苗接种可能构成一种新的免疫策略，为免疫低下的老年人群提供有效的保护，使其免受流感感染。在这个项目中，我们提出了以下具体目标： 目的1.确定IC调节免疫反应的机制 目的2.研究Fc受体选择性信号对免疫应答的调节作用 目的3.确定1C疫苗在克服年龄相关性免疫缺陷方面的有效性。

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.