Fc Receptor Signaling in Vaccine Design for the Elderly

描述（由申请人提供）：在老年人中，细胞和体液免疫均显著下降，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，并导致老年人对感染的易感性增加。此外，免疫衰老是老年人对疫苗接种反应性降低的原因。因此，老年人特别脆弱，在发生生物恐怖袭击时面临更大的风险。老年人对流感病毒感染和疫苗接种的反应受损可能与临床最相关。老年人对流感疫苗接种的反应明显受损。老年人对流感疫苗接种的第一和第二抗体反应都减弱。即使流感疫苗和流行病毒之间的抗原匹配非常接近，接种疫苗也只能为年龄≥ 65岁的受试者提供30%- 40%的保护，而年龄< 65岁的受试者则为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特别无效，这突出表明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，并且在免疫应答的激活和调节中具有关键功能。我们最近的研究表明，免疫复合物（IC）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应答中与年龄相关的缺陷。我们还证明了抑制性Fc受体Fc γ IIB可以通过使用小干扰RNA（siRNA）的RNA干扰来选择性地消融。因此，操纵FcR信号和IC疫苗接种可能构成一种新的免疫策略，以提供有效的保护免疫受损的老年人群免受流感感染。在这个项目中，我们提出以下具体目标： 目标1。确定IC调节免疫应答的机制 目标二。研究通过选择性信号传导Fc受体调节免疫应答 目标3。确定1C疫苗在克服年龄相关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.