EXPRESSION OF TUBERCULOSIS IN THE LUNG

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Alveolar Macrophages (AM) are the first line of cellular defense against inhaled infectious agents such as MTB. Yet almost nothing is known about the capacity of AM from healthy or TB patients to ingest and inhibit the growth of MTB. Our preliminary data indicate that the effector function of AM for avirulent MTB exceeds that of blood monocytes (MN), in part because of increased release of tumor necrosis factor-alpha (TNF) which serves as a macrophage activating factor (MAF). By contrast, AM are weak producers of transforming growth factor beta (TGFbeta), a deactivating cytokine. Mononuclear phagocytes in tuberculous granulomas, however, express TGFbeta, as do MN from TB patients. AM from healthy subjects are primed for effector function against MTB, but TB may be associated with release of deactivating cytokines such as TGFbeta. AM from healthy subjects nonspecifically suppress T lymphocyte responses to antigenic and mitogenic stimuli. During TB, MN specifically suppress T cell responses to tuberculin purified protein derivative (PPD) possibly through increased TGFbeta which is immunosuppressive. Also during TB, peripheral blood mononuclear cells (PBMC) are non responsive to the secreted 30 kD antigen (alpha ag) of MTB; as the alpha ag is a direct stimulus for cytokine production by MN, this unresponsiveness may be due to cytokine- induced suppression by MN. These considerations lead us to the hypothesis that in TB, AM are specifically suppressive of T cell responses to PPD (and the alpha ag) and deactivated for killing of the organism through increased expression of cytokines such as TGFbeta. Together, and separately, immunosuppression and decreased effector function contribute to the pathogenesis of TB in the lung. TB afflicts HIV-infected persons early in their course while tuberculin skin tests are still positive and CD4'counts relatively intact suggesting that disturbances in effector function against MTB may be operant. We hypothesize that these AM are defective in killing of MTB due to increased expression of deactivating cytokines which override MAFs. Th1-type cytokines are protective in certain animal models. We hypothesize that in TB granulomas, macrophages express deactivating cytokines such as TGFbeta and T cells fail to optimally express a Th1-type pattern of cytokines. In TB granulomas from HIV-infected persons, the cellular architecture is distorted with a further decrease in Th1-type cytokines produced by T cells; concurrent production of deactivating cytokines by mononuclear phagocytes leads to an inexorable increase in load of AFB within granulomas. The Specific Aims to test these hypotheses are: l. To examine the immunosuppressive activity and mediators of suppression of AM from patients with pulmonary TB for blood T cell responses to tuberculin PPD and the alpha ag; and to compare alveolar and blood lymphocyte responsiveness to these stimuli including production of Th1 and Th2 cytokines, and their respective cytotoxicity for antigen-pulsed and MTB-infected AM. 2. To assess the intracellular growth of virulent MTB in AM from patients with TB; their production of and response to macrophage activating and deactivating cytokines; and the modulatory effects of HIV infection. 3. To characterize the cellular architecture and the pattern of cytokine expression in pulmonary granulomas from patients with TB with or without HIV using the complementary approaches of immunofluorescence, RNA PCR, in situ hybridization, and immunohistochemistry.