TH1 CYTOKINES AND IMPAIRED CD8* CTLS IN ELDERLY

描述（改编自申请人的摘要）：本发明的目的是为了描述本发明。 建议是确定缺乏细胞毒性T细胞的机制， 老年人淋巴细胞（CD 8 + CTL）抗流感病毒活性 以及如何纠正这种缺陷。 老年人代表 严重流感、肺炎和死亡的高危人群。 的 疾病控制中心估计，多达40，000例流感相关 每年流感流行期间都会发生死亡;其中90%以上 死亡发生在65岁以上的人群中（死亡率和死亡率周刊 Report，Vol.3，No. RR-3，April 21，1995）。 现在很清楚，CD 8 + CTL 活动在严重流感病毒的恢复中起着重要作用 感染和疾病。 不幸的是，老年人通常表现出 与对照组相比，CD 8 + CTL对流感病毒的应答显著降低。 年轻，为发生长期和更严重的 感染. 然而，这种与年龄相关的CD 8 + CTL缺陷的原因是 不知道。 细胞介导的免疫由两大类免疫调节因子控制。 细胞因子 Th 1细胞因子，如干扰素γ（IFN-g）、白细胞介素 2（IL-2）和白细胞介素12（IL-12）有利于CD 8 + CTL的诱导，而 Th 2细胞因子，如白介素4（IL-4）和白介素10（IL-10） 禁止他们。 初步结果显示，老年人的T淋巴细胞 人产生相对较少的IFN-γ和更多的IL-4时，刺激 体外流感病毒。 类似的结果已经在旧的 小鼠，表明这些细胞因子在决定 老年人CD 8 + CTL的活性。 调查人员建议， 老年人中CD 8 + CTL活性缺乏的潜在机制是 年龄相关的从主要产生Th 1细胞因子到产生Th 2细胞因子的转变 细胞因子 Th 1细胞因子的这种损失导致CD 8 + T细胞的数量减少。 表达CD 28的CTL，一种必需的共刺激分子， 穿孔素-颗粒酶介导的裂解活性降低， 无能记忆性CD 8 + T（CD 45 RO +/CD 28）细胞。 利用我们的良好特性， 体外流感CTL模型，计划测试CD 8 + CTL的诱导 流感病毒特异性活性，以确定老年人队列 CTL反应降低的人。 然后将确定CD 8 + CTL是否 从这些也表达减少的IFN-g（Th 1）和增加的IL-4和IL-10 (Th2)表达CD 28的CD 8+细胞的频率较低， 穿孔素和颗粒酶的合成，IL-12刺激IFN-γ的产生， 增强CD 8 + CTL活性。 因此，如果治疗老年人的T细胞， 具有IL-12的CTL活性缺陷的人导致IFN-g增加 生产，并在恢复CD 8 + CTL活性（如建议从 结果在有限的研究），那么假设缺乏Th 1细胞因子， 生产的原因是CTL缺乏症的老年人将是正确的。 另外，老年人CD 8 + CTL缺陷可能是由于Th 1缺陷所致。 精氨酸介导的信号转导（JAK/STAT酪氨酸磷酸化） 在CD 8 + T细胞中。 如果Th 1细胞因子开关被证明是 老年人CD 8 + CTL缺乏的潜在机制， 细胞因子免疫疗法或用标准流感病毒配制细胞因子 疫苗的设计可能是为了开发更有效的 针对流感和其他呼吸道感染的免疫预防， 高危老人。

DESCRIPTION (Adapted from the Applicant's Abstract): The objectives of this proposal are to determine the mechanisms of deficient cytotoxic T lymphocytes (CD8+ CTL) activity against influenza virus among elderly persons and how this deficiency can be corrected. Elderly persons represent a high risk group for severe influenza disease, pneumonia and death. The Centers for Disease Control estimates that up to 40,000 influenza-associated deaths occur during each yearly influenza epidemic; more then 90% of these deaths occur among persons >65 years of age (Morbidity and Mortality Weekly Report, Vol. 3, No. RR-3, April 21, 1995). It is now clear that CD8+ CTL activity plays a major role in the recovery from severe influenza virus infection and disease. Unfortunately, elderly persons generally exhibit significantly lower CD8+ CTL responses to influenza virus relative to the young, providing a basis for occurrence of prolonged and more severe infections. However, the cause of this age-related CD8+ CTL deficiency is not known. Cell-medicated immunity is controlled by two major categories of cytokines. The Th1 cytokines, such as interferon gamma (IFN-g), interleukin 2 (IL-2) and interleukin 12 (IL-12), favor the induction of CD8+ CTLs while Th2 cytokines, such as interleukin 4 (IL-4) and interleukin 10 (IL-10) inhibit them. Preliminary results show that T lymphocytes from elderly persons produce relatively less IFN-gamma and more IL-4 when stimulated with influenza virus in vitro. Similar results have been demonstrated in old mice, suggesting that these cytokines play a pivotal role in determining the activity of CD8+ CTL in the elderly. The investigators propose that the mechanism underlying the deficient CD8+ CTL activity among the elderly is an age-related switch from producing predominantly Th1 cytokines to Th2 cytokines. This loss of Th1 cytokines results in reduced numbers of CD8+ CTLs expressing CD28, an essential costimulatory molecule and also in reduced perforin-granzyme-medicated lytic activity and accumulation of anergic memory CD8+ T (CD45RO+/CD28) cells. Using our well characterized in vitro influenza CTL model, plans are to test for induction of CD8+ CTL activity specific for influenza virus to identify a cohort of elderly persons with reduced CTL responses. It will then be determined if CD8+ CTL from these also express decreased IFN-g (Th1) and increased IL-4 and IL-10 (Th2) production, lower frequency of CD8+ cells expressing CD28 and reduced perforin and granzyme synthesis, IL-12 stimulates IFN-g production and enhances CD8+ CTL activity. Therefore, if treatment of T cells from elderly persons with deficient CTL activity with IL-12 results in increased IFN-g production, and in the restoration of CD8+ CTL activity (as suggested from results in limited studies), then the hypothesis that deficient Th1 cytokine production is the cause of CTL deficiency in the elderly would be correct. Alternatively, elderly CD8+ CTL deficiency may be due to defective Th1 cytokine-mediated signal transduction (JAK/STAT tyrosine phosphorylation) pathways in the CD8+ T cells. If the Th1 cytokine switch is shown to be the mechanism underlying the CD8+ CTL deficiency in elderly persons, then cytokine immunotherapy or formulation of cytokines with standard influenza vaccines may be designed for the development of more effective immunoprophylaxis against influenza and other respiratory infections for high risk elderly persons.