EXPRESSION OF ANTIMYCOBACTERIAL IMMUNITY

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DESCRIPTION (Adapted from the applicant's abstract): SCID mice are the model for the proposed experiments. These mice are incapable of T cell-mediated immunity and are therefore incapable of withstanding infection with the BCG strain of Mycobacterium bovis. However, SCID mice can be rescued from an already established BCG infection by infusing them with spleen cells or CD4+ T cells from naive coisogenic C.B-17 donors. On the other hand, SCID mice already infected with virulent M. tuberculosis are more difficult to rescue, particularly in the lungs. Based on these observations, the applicant proposes (i) to study the immunological mediation of this rescue in terms of the cellular and molecular events that occur at sites of already established mycobacterial infection, with the purpose of determining why rescue of infections in the lungs are less efficient than in the organs. (ii) The host cells that extravasate into infected organs will be identified, their relative proportion determined, as well as the temporal relationship of their extravasation, with the generation of specific CD4+ T-cell mediated immunity. The acquisition of specific immunity will be monitored in terms of the development of DTH to PPD, resistance to secondary challenge, and the presence of CD4+ T cells capable of adaptively immunizing SCID recipients. The applicant also proposes to identify the key adhesin molecules used by CD4+ T cells to enter sites of infection, as well as adhesion molecules used by macrophages to enter these sites to form granulomas and to maintain the integrity of them over time. This approach will involve the use of monoclonal antibodies against major leukocyte integrins and their ligands in an attempt to block the expression of immunity in the lungs and elsewhere. Macrophage activation in granulomas associated with rescue from infection will be measured in terms of production of reactive nitrogen intermediates and Ia expression.