While influenza vaccine greatly decreases the risk of influenza-induced and secondary pneumonias, its efficacy in preventing influenza disease is markedly reduced in the elderly, relative to the young. Numerous studies have established decreases in antibody titers, T cell proliferation, cytotoxic responses, and altered cytokine production after influenza immunization in the elderly. A prevalent design for vaccines against viral infections is to induce sufficient quantities of appropriate antibodies that neutralize virus at the site of viral entry before infection is established. If, however, virus is not completely neutralized at the site of entry, the question remains: what form of immune response will limit viral spread before disease symptoms can be induced? The premise of this proposal is that antibody cannot prevent infection in all cases since cytotoxic T (CD8+CTL) cells are needed to limit viral spread during primary influenza virus infection. The investigators' data indicate that, after influenza immunization, CD8+ cells of the elderly show reduced activation marker expression and decreased expansion upon culture with influenza antigen. They now propose that a decrease in influenza-specific CD8+ responses is a major reason for ineffective influenza vaccination in the elderly. It has been technically impossible to assess CD8+CTL responses in large vaccine clinical trials due to the rigors of cytotoxicity assays. However, such clinical trials are now possible using recently developed flow cytometric assays with peptide-loaded MHC Class I tetramers to quantitate peptide-specific CD8+CTL. Prior to such trials, however, it must be established that cytotoxic activity and CTL numbers, as determined by flow cytometry, are strongly correlated. It must also be established that differences exist between young and elderly in CD8+CTL numbers, as determined by tetramer analysis. The current proposal hypothesizes that decreased efficacy of influenza immunization inthe elderly is due to decreased cell-mediated immune responses to the vaccine, with a primary defect in CD8+ cells.
The specific aims are to: 1) Determine if differences exist between young and elderly in CD8+ T cell responses to influenza vaccination. Direct quantitation and phenotypic analysis of influenza-specific CD8+ T cells will be performed using influenza-peptide loaded Class I A2 tetramers and multi-parameter flow cytometry. Associations between the results of this assay and cytotoxicity assays, antibody production, T cell proliferation, and cytokine production after in vitro culture with influenza antigens will be evaluated. 2) Investigate the mechanism of altered CD8+ T cell responses in the elderly. They will examine influenza-specific CD8+ cells for: i) kinetics of induction; ii) epitope dominance of the response; iii) proliferative and cytotoxic potential; iv) phenotypic markers, i.e., activation, memory/naive, co-stimulatory, and apoptotic. And 3) Determine the role of CD8+ T cells in age-associated alterations in IFN-gamma production after influenza vaccination.
|Gardner, Elizabeth M; Gonzalez, Elizabeth W; Nogusa, Shoko et al. (2006) Age-related changes in the immune response to influenza vaccination in a racially diverse, healthy elderly population. Vaccine 24:1609-14|
|Gardner, Elizabeth M; Murasko, Donna M (2002) Age-related changes in Type 1 and Type 2 cytokine production in humans. Biogerontology 3:271-90|