PATHOGENESIS OF CHRONIC LUNG DISEASE

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The alveolar macrophage constitutes the first line of defense within the lung against a number of facultative intracellular parasites. One of the most important of these is the tubercle bacillus. This study will examine the role played by these resident phagocytic cells and their emigrant mononuclear counter parts, which enter the developing lung tubercle in large numbers during the expression and modulation of the immune response. The specific aims of this study are directed towards understanding the cellular interactions which occur within the chronically infected lung in an attempt to explain the paradox of continued survival by the primary mycobacterial population within the lung and its draining lymph nodes, in the face of clear evidense of a protective cell-mediated immunity being expressed elsewhere in the reticuloendothelial system. This state of affairs seems particularly true for mice infected with M. kansasili or M. simiae. The first aim of this study will be to examine the role of T-cell subsets in the induction and expression of delayed hypersensitivity and antituberculous immunity within the aerogenically infected host. The T-cell responses will be measured within the lungs of adoptively immunized, T-cell depleted mice using lymphocytes characterized with respect to their Lyt 1+ or Ly 23+ surface markers. The relative makeup of this population will be correlated with their functional characteristics such as expressor, memory, or suppressor cell activity in both hypersensitive and anergic donors. The second objective will be to determine the effect of adoptive transfer of T-cells on the kinetics of the mononuclear cell response in unilaterally pulsed parabiotic mouse lungs. The effect of immune T-cells on macrophage activation within the chronically infected alvoelar tissues will be examined in terms of their killing activity when the activated macrophages are infected with the atypical mycobacteria. Finally, mice will be sensitized with an extracellular protein immunogen which is released by the actively multiplying mycobacteria, both in vivo and in vitro. The effect of increasing the dose of immunogen when it is presented to mice in different adjuvanting preparations will be assessed in terms of delayed hypersensitivity, acquired resistance and tolerance induction. Such studies will provide further insights into the cellular interactions involved in the modulation of the host response within the lung following an infection with one of these important human pathogens.