ABSTRACT
Profiles of intercellular adhesion molecule-1 (ICAM-1) expression on murine peritoneal macrophages (M phi s) infected with Mycobacterium leprae during cultivation were examined with special reference to the regulatory effects of tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta). When M phi s were infected with M. leprae or stimulated with heat-killed M. leprae at day 0, their ICAM-1 expression, measured in terms of the ratio of M phi s positively stained with anti-ICAM-1 antibody (Ab), rapidly increased, peaking during days 1 to 3 and thereafter fell, returning to the normal level by day 7. The addition of TNF-alpha or anti-TGF-beta Ab inhibited the middle phase (day 7) downregulation of M phi ICAM-1 expression, although the late-phase (day 14) downregulation of ICAM-1 was not prevented by them. M. leprae-infected M phi s released small amounts of TNF-alpha and significant amounts of TGF-beta into the culture medium. This may indicate that M. leprae-infected M phi s produced the majority of TNF-alpha in a membrane-bound form. Alternatively, endogenous TNF-alpha might upregulate M phi ICAM-1 expression even at very low concentrations. In any case, these findings indicate the central roles of TNF-alpha and TGF-beta in the early phase upregulation and the middle-to-late phase downregulation, respectively, of ICAM-1 expression by M. leprae-infected M phi s.
Subject(s)
Tumor Necrosis Factor-alpha/physiology , Tumor Necrosis Factor-alpha/immunology , Macrophages/immunology , Macrophages/microbiology , Mycobacterium leprae/physiology , Mycobacterium leprae/immunologyABSTRACT
In the present study, we evaluated the in vivo anti-Mycobacterium leprae activities of KRM-1648 (KRM) given at long intervals in combination with ofloxacin (OFLX), clofazimine (CFZ), and dapsone (DDS). We also examined the combined effects of two biological response modifiers (BRMs), gamma interferon (IFN-gamma) and granulocyte-macrophage colony-stimulating factor (GM-CSF), on the therapeutic efficacy of KRM. KRM exhibited potent therapeutic efficacy against M. leprae infection in mice even when given at 4-week intervals. KRM displayed increased efficacy in combination with OFLX, CFZ, and DDS (given three or six times per week) when given to mice in the multidrug combination KRM + OFLX + CFZ + DDS. The therapeutic efficacy of KRM given at 4-week intervals was increased by combined use with IFN-gamma but not by GM-CSF. Adoptive transfer of M. leprae antigen-primed lymphocytes of euthymic mice to recipient athymic nude mice with progressive M. leprae infection markedly enhanced host resistance.