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.
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