Modulation of immune senescence by androgen treatment in aged male macaques

描述(申请人提供)：衰老导致免疫功能进行性下降，从而导致与感染相关的发病率和死亡率增加。在男性中，年龄的增加还会导致循环中雄激素(睾酮和脱氢表雄酮(DHEA))水平的显著变化，这与骨质疏松症、心血管疾病和糖尿病有关。由于性类固醇水平调节免疫功能，与年龄相关的雄激素水平下降很可能也会影响免疫衰老。尽管约70%的80岁以上男性符合性腺功能减退的临床定义，但对这一人群的治疗仍存在争议。然而，在美国，睾丸素处方的数量急剧增加，2011年达到560万张。因此，我们必须更好地了解补充雄激素对老年男性的多效性作用。乌尔班斯基博士(合作者)开发了一种雄激素替代的新范例，其中睾酮和DHEA被用来模拟这些激素的自然昼夜节律。这种方法可以使老年雄性恒河猴的睾丸激素和脱氢表雄酮水平恢复到“年轻”的24小时节律。我们建议使用这一高度创新的范式来测试这一假设，即生理性睾酮补充，旨在模拟幼年动物的循环24小时模式，将改善免疫衰老的主要生物标志物，并提高T细胞对疫苗接种的反应。我们将首先通过以下评估来确定生理性雄激素补充对免疫衰老严重程度的影响：1)幼稚和记忆T和B细胞亚群的频率；2)胸腺输出；3)血浆关键炎性细胞因子水平；以及4)T细胞和5)先天免疫细胞产生炎性细胞因子。然后，我们将通过测量：1)T和B细胞增殖的动力学和大小；2)反应T细胞的频率；以及3)抗体滴度，来表征生理性雄激素补充对接种改良的安卡拉牛痘疫苗和季节性流感疫苗后的抗病毒免疫反应的影响。最后，我们将通过测定1)T和B细胞亚群在骨髓、淋巴结、支气管肺泡灌洗和肠道活检中的分布，以及2)这些组织的细胞因子环境，来检验补充雄激素对组织驻留淋巴细胞动态平衡的影响。这些研究将与乌尔班斯基博士的实验室密切合作，并利用一项由美国国立卫生研究院资助的R01研究(R01 AG-036670)，该研究正在调查补充雄激素对老年雄性猕猴认知表现和昼夜睡眠-觉醒周期的影响。通过研究同样的动物，我们将能够进行二次分析，以揭示老年灵长类动物免疫和神经内分泌功能之间的额外关联。这些努力有可能提供一种新的治疗方法来提高不断增长的老年人口的免疫力。

DESCRIPTION (provided by applicant): Aging results in a progressive decline in immune function, which leads to increased morbidity and mortality related to infections. In men, increasing age also results in significant perturbations in the levels of circulating androgens (testosterone and dehydroepiandrosterone (DHEA)), which has been linked to sarcopenia, osteoporosis, cardiovascular disease and diabetes. Since sex steroid levels modulate immune function, it is likely that the age-related decline in androgen levels will also affect immune senescence. Although ~70% of men over the age of 80 meet the clinical definition of hypogonadism, there is controversy over treating this population. Nevertheless, the number of testosterone prescriptions has increased dramatically in the US reaching 5.6 million in 2011. Thus, it is critical that we gain a better understanding of the pleiotropic effects of androgen supplementation in aged men. Dr. Urbanski (co-PI) has developed a novel paradigm of androgen replacement in which testosterone and DHEA are administered to mimic the natural circadian rhythm of these hormones. This approach can restore both testosterone and DHEA levels to "youthful" 24-hour rhythms in aged male rhesus macaques. We propose to use this highly innovative paradigm to test the hypothesis that physiological testosterone supplementation, designed to mimic the circulating 24- hour pattern of young animals, will ameliorate major biomarkers of immune senescence and improve T cell responses to vaccination. We will first determine the impact of physiological androgen supplementation on the severity of immune senescence by assessing: 1) the frequency of naive and memory T and B cell subsets; 2) thymic output; 3) plasma levels of key inflammatory cytokines; and inflammatory cytokine production by 4) T cells and 5) innate immune cells. We will then characterize the impact of physiological androgen supplementation on the anti-viral immune response following vaccination with modified vaccinia ankara as well as the seasonal influenza vaccine by measuring: 1) kinetics and magnitude of T and B cell proliferation; 2) frequency of responding T cells; and 3) IgG antibody titer. Finally, we will examine the impact of androgen supplementation on the homeostasis of tissue resident lymphocytes by determining 1) T and B cell subset distribution in bone marrow, lymph nodes, bronchoalveolar lavage, and gut biopsies; and 2) the cytokine milieu of these tissues. These studies will be carried out in close collaboration with Dr. Urbanski's laboratory and leverage a funded NIH R01 study (R01 AG-036670) that is investigating the impact of androgen supplementation on cognitive performance and circadian sleep-wake cycles in aged male macaques. By studying the same animals, we will be able to carry out secondary analyses to uncover additional correlations between immunity and neuro- endocrine function in the aged primate. These efforts have the potential to provide a new therapeutic approach to improve immunity in the growing elderly population.