Aging and Immunity to Infections

描述(申请人提供)：随着人类寿命的增长，越来越迫切地需要了解老龄化对感染免疫力的影响，并制定预防或治疗策略来抵消与年龄相关的免疫力下降。持续病毒感染的免疫控制是与衰老有关的一个问题，正如有充分记录的老年人阿尔法疱疹病毒重新激活导致带状疱疹后遗神经痛(带状疱疹)的例子所表明的那样。人类γ-疱疹病毒，即Epstein-Barr病毒和Kaposi肉瘤相关疱疹病毒，是重要的人类病原体，与淋巴增生性疾病和多种恶性肿瘤有关，包括Burkitt淋巴瘤、霍奇金病、鼻咽癌和Kaposi肉瘤。因此，我们必须了解老年人控制这些感染的能力。在目前的方案中，我们将利用一个特性良好的小鼠模型HV68，来研究衰老对这类重要的持久性病毒的免疫控制的影响。越来越多的数据表明，CD4T细胞、CDS T细胞和抗体都有助于免疫控制幼鼠的病毒潜伏期。我们的初步数据显示，病毒特异性抗体滴度在感染后保持两年以上，但随着年龄的增长，中和活性逐渐下降。为了解这一引人注目且新颖的观察结果背后的功能暗示和机制，拟议的实验在本补充申请的三个具体目标中概述。在目标1中，我们将确定递减中和抗体对老年小鼠持续的y-疱疹病毒感染的免疫控制的功能影响。在目标2中，我们将确定与老年小鼠中和活性下降相关的抗体和病毒特异性B细胞和浆细胞的差异。在目标3中，我们将确定中和抗体下降的潜在机制。我们将确定与年龄相关的CD4功能下降的影响，并确定中和滴度下降是否是持久性病毒独有的。这些研究不仅对老年人持续性感染的免疫控制有意义，而且对理解长期维持体液免疫的机制也有普遍意义。 随着人们年龄的增长，他们的免疫功能会下降。这在他们处理新感染和有效接种疫苗的能力方面意义重大，但对他们保持对持续感染的免疫控制的能力也是重要的。水痘病毒在老年人体内重新激活导致带状疱疹就是一个经典的例子。在这个项目中，我们将研究年龄对另一组持久性病毒-伽马疱疹病毒免疫控制的影响，这类病毒与几种类型的癌症的发展有关。我们将使用老鼠模型，在其中我们可以进行人类不可能进行的良好控制的研究。

DESCRIPTION (provided by applicant): With the increasing longevity of the human population, there is increased urgency to understand the consequences of aging on immunity to infections and to develop preventative or therapeutic strategies to counteract age-associated immune decline. Immune control of persistent viral infections is a problem associated with aging, as illustrated by the well-documented example of reactivation of the alpha-herpesvirus, varicella-zoster in the elderly, causing postherpetic neuralgia (Shingles). The human gamma-herpesviruses, Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus, are important human pathogens, associated with lymphoproliferative disorders and various maligancies, including Burkitt's lymphoma, Hodgkin's disease, nasopharyngeal carcinoma and Kaposi's sarcoma. It is therefore critical that we understand the ability of aged individuals to control these infections. In the current proposal, we will exploit a well-characterized mouse model, HV68, to study the impact of aging on immune control of this important class of persistent viruses. Accumulating data suggest that CD4 T cells, CDS T cells and antibodies all contribute to immune control of viral latency in young mice. Our preliminary data show that virus-specific antibody liters are maintained for over two years after infection, but that there is a progressive decline in neutralizing activity with age. Proposed experiments to understand the functional implications and mechanisms underlying this striking and novel observation are outlined in three specific Aims in this supplemental application. In Aim 1, we will determine the functional impact of declining neutralizing antibodies for immune control of a persistent y-herpesvirus infection in aged mice. In Aim 2, we will identify differences in the antibody and virus-specific B cells and plasma cells associated with declining neutralizing activity in aged mice. In Aim 3, we will identify mechanisms underlying the decline in neutralizing antibodies. We will determine the impact of the age-associated decline in CD4 function and determine whether declining neutralizing titers are unique to persistent viruses. These studies have implications not only for immune control of persistent infections in aged individuals, but may also have general implications for understanding mechanisms for long-term maintenance of humoral immunity. As people age, their immune function declines. This is significant in terms of their ability to handle new infections and to be effectively vaccinated, but also for their ability to maintain immune control of persistent infections. The reactivation of the chicken pox virus in the elderly to cause Shingles is a classic example. In this project we will study the impact of age on immune control of another group of persistent viruses, the gamma-herpesviruses, which are associated with the development of several types of cancer. We will use a mouse model, in which we can carry out well-controlled studies not possible in humans.