Aging is associated with a dramatic increase in serious complications of influenza. Recent studies have linked influenza to excess mortality from cardiovascular diseases and pneumonia and influenza. Interactions between the immune system and influenza that lead to these events are not well understood but may have an inflammatory basis that is modified by influenza vaccination to prevent these complications. However, the loss of vaccine efficacy with aging and rising hospitalization and death rates due to influenza in spite of widespread vaccination programs call for significant improvements in current vaccines. Translational research methods are needed to identify reversible changes in the T-cell response that are poorly stimulated by current vaccines and can be targeted for future development of vaccines and immunotherapy. The purpose of this project is to identify T helper cell (Th) and cytotoxic T lymphocyte (CTL) responses to influenza that predict risk of influenza illness in older adults. The central hypothesis is the increased risk of influenza illness in older adults is due to a diminished CTL response to influenza vaccination. This CTL response is dependent on a Th1 response to vaccination that reverses the age-related shift toward Th2 responses. This 5-year proposal will compare responses to influenza vaccination in older adults who develop influenza illness versus those who do not, and identify changes in T-cell responses with aging, ischemic heart disease and congestive heart failure that increase influenza risk under the following specific aims: 1) Identify changes in Th1/Th2 and CTL responses that are linked to the development of influenza illness, 2) Elucidate the mechanisms by which T-cell responses to vaccination modify risk for influenza illness. 3) Test heat shock proteins (Hsp) as potential vaccine adjuvants to enhance the CTL response to vaccination.
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