Tuberculosis is still relatively common in the elderly, probably reflecting the very high incidence of skin test positivity of the population in the first third of the century, and the fact that many of these individuals are still alive and generally healthy at the present time. As they age, however, such individuals run the risk of developing recrudescence of latent tuberculosis, while nonsensitized individuals run the risk [especially if institutionalized] of contracting a primary tuberculosis infection. The basis of the susceptibility of the aged to tuberculosis infection or recrudescent disease is still poorly understood, but is believed to reflect age-associated changes in the cell-mediated immune response to the organism. Work specifically in the investigator's laboratory supports this contention by showing a series of defects in the CD4 TH1 IFN-secreting T cell pathway associated with protection and memory immunity to the disease. Hence, using a realistic low dose aerosol infection model in aging mice, the investigators have identified specific lesions such as the low expression of adhesion markers on CD4 T cells, and the absence of a pulmonary IL-12 response needed to enhance IFN secretion by such cells. In the proposed study, they intend to continue to define the cellular response in the old lung to tuberculosis, including the use of new markers such as CD49E and CD95. In addition, they intend to resolve the nature of the recrudescent event, framed on new evidence that the capacity of a given M.tuberculosis isolate to promote local TNF and chemokine production may directly correlate with the nature of the granuloma response and its potential breakdown as the mouse ages. Further issues to be addressed include the role of the predominant TH2/IL-4 environment in old mice [an environment that includes unusual IL-4 secreting CD4+NK1. 1+ and CD8+ T cell populations] in potential interference with TH1 responses, which they will investigate in part by using aging IL-4 gene disrupted mice, and the potential reversal or delay of endogenous reactivation of disease in the old lung by administration of a sub-unit vaccine preparation.
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