TH1 CYTOKINES AND IMPAIRED CD8* CTLS IN ELDERLY

描述(改编自申请人的摘要)：本报告的目的 建议确定细胞毒性T细胞缺陷的机制 老年人淋巴细胞(CD8+CTL)抗流感病毒活性的研究 以及如何纠正这一缺陷。老年人代表着 严重流感、肺炎和死亡的高危人群。这个 疾病控制中心估计，多达4万人与流感有关 每年的流感流行期间都会发生死亡事件；其中90%以上 死亡发生在65岁的人群中(《发病率和死亡率周刊》 报告，第3卷，第RR-3,1995年4月21日)。现在很明显，CD8+CTL 活动对严重流感病毒的康复起着重要作用 感染和疾病。不幸的是，老年人通常会 与流感病毒相比，CD8+CTL反应显著降低 年轻，为长期和更严重的发生提供了基础 感染。然而，这种与年龄相关的CD8+CTL缺陷的原因是 不知道。细胞药物免疫由两个主要类别控制 细胞因子。Th1细胞因子，如干扰素-γ、白细胞介素2 2(IL-2)和IL-12(IL-12)有利于CD8+CTL的诱导 Th2细胞因子，如白介素4(IL-4)和白介素10(IL-10) 抑制他们。初步结果显示，老年人的T淋巴细胞 当人受到刺激时，产生的干扰素-γ相对较少，产生的IL-4较多 流感病毒在体外。类似的结果在老年人身上也得到了证明。 小鼠，表明这些细胞因子在决定 老年人CD8+CTL活性的研究调查人员提出， 老年人CD8+CTL活性低下的机制是 与年龄相关的从主要产生Th1细胞因子向Th2细胞因子的转变 细胞因子。Th1细胞因子的这种丧失导致CD8+的数量减少 表达CD28的CTL，CD28是一种重要的共刺激分子，在 穿孔素-颗粒酶抑制穿孔素-颗粒酶的溶解活性和蓄积 无能记忆CD8+T(CD45RO+/CD28)细胞。使用我们精心设计的 体外流感CTL模型，计划检测CD8+CTL的诱导 识别一组老年人的流感病毒特异性活性 CTL反应减弱的人。然后将确定CD8+CTL是否 从这些细胞还表达降低的干扰素-γ(Th1)，增加IL-4和IL-10 (Th2)产生，CD8+细胞表达CD28的频率降低 穿孔素和颗粒酶的合成，IL-12刺激干扰素-g的产生和 增强CD8+CTL活性。因此，如果治疗来自老年人的T细胞 IL-12缺乏CTL活性的人会导致干扰素-g升高 生产，并恢复CD8+CTL活性(如从 结果有限的研究)，然后假设缺乏Th1细胞因子 生产是导致老年人CTL缺乏的原因会是正确的。 或者，老年人CD8+CTL缺乏可能是由于Th1缺陷所致 细胞因子介导的信号转导(JAK/STAT酪氨酸磷酸化) CD8+T细胞的信号转导途径。如果Th1细胞因子开关被证明是 老年人CD8+CTL缺乏的机制 标准流感的细胞因子免疫治疗或细胞因子配方 疫苗的设计可能会为开发出更有效的 预防流感和其他呼吸道感染的免疫预防 高危老年人。

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.