INFECTION MODEL OF LEPROMATOUS LEPROSY

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Mycobacterium avium-complex can produce progressive systemic infections in susceptible strains of mice (C57BL/6 or BALB/c) which resemble human lepromatous leprosy, providing a convenient experimental model with which to study the immunology of the antileprosy response. The role of different Tcell subsets in this process can now be defined in adoptively immunized animals receiving specific Tcell subsets and cloned Tcells. The latter provide an important probe for investigating the nature of the epitopes responsible for the induction of delayed hypersensitivity and acquired resistance in the infected host. The first aim is to study the kinetics of the Tcell response leading to the expression of DTH and CMI to M. aviumintracellulare infections, and to T-cell memory induction, using both T-cell lines and clones (human and murine). T-cell responses in susceptible vs. resistant mouse strains will be compared quantitatively using appropriate adoptive transfer models. Attempts will be made to assess T-cell clones in functional terms wherever possible. The second aim will continue studies examining the number and activation of macrophages within the heavily infected lung, spleen or footpad following infection of subsceptible, resistant mice with virulent and attenuated M. avium. The proposed studies will compare the phagocytic activity and bactericidal ability of resident, immune and immuneboosted macrophages tested both in vitro and in vivo against a variety of different test organisms. Activation of macrophages by lymphokines added in vitro will be compared with in vivo activated cells. The third aim will examine the ability of protein sensitins from M. tuberculosis and M. aviumintracellualare to activate Tcell clones derived from immune and tuberculin sensitive hosts. The sensitin(s) will be separated by HPLC and Western blotting and tested for their ability to induce DTH response in vaccinated mice, as well as blastogenic responses by Tcell clones tested in vitro. Sensitins will be tested as immunogens by coupling to sheep erythrocytes, to nitrocellulose membranes or to live BCG and tested for DTH and CMI. These studies will provide valuable new data on the restoration of cellmediated immunity in chronically infected mice.