Interleukin (IL)-12 Deficiency in Susceptible Mice Infected with Mycobacterium avium and Amelioration of Established Infection by IL-12 Replacement Therapy

Kobayashi, Keiko; Yamazaki, Junko; Kasama, Tsuyoshi; Katsura, Takashi; Kasahara, Keita; Wolf, Stanley F.; Shimamura, Tadakatsu

doi:10.1093/infdis/174.3.564

Cited by 32 publications

(17 citation statements)

References 47 publications

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“…TDM can stimulate production of IL-12 from mouse macrophages (24), and IL-12 is found in the active lesion elicited by experimental mycobacterial infection in mice, including that with Mycobacterium avium (17,18) and Mycobacterium leprae (16). In immunized mice challenged with TDM, lesional IL-12 and IFN-␥ reached peak levels concomitantly 3 days after challenge, whereas unimmunized mice express less of them.…”

Section: Discussionmentioning

confidence: 99%

Trehalose 6,6′-Dimycolate (Cord Factor) ofMycobacterium tuberculosisInduces Foreign-Body- and Hypersensitivity-Type Granulomas in Mice

Yamagami¹,

Matsumoto²,

Fujiwara³

et al. 2001

Infect Immun

101

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Granulomatous inflammation is characterized morphologically by a compact organized collection of macrophages and their derivatives. It is classified as either a hypersensitivity type or a foreign-body type. Lipid components of the Mycobacterium tuberculosis cell wall participate in the pathogenesis of infection. Strains of M. tuberculosis have cord factor (trehalose 6,6-dimycolate [TDM]) on their surface. To clarify host responses to TDM, including immunogenicity and pathogenicity, we have analyzed the footpad reaction, histopathology, and cytokine profiles of experimental granulomatous lesions in immunized and unimmunized mice challenged with TDM. In the present study, we have demonstrated for the first time that TDM can induce both foreignbody-type (nonimmune) and hypersensitivity-type (immune) granulomas by acting as a nonspecific irritant and T-cell-dependent antigen. Immunized mice challenged with TDM developed more severe lesions than unimmunized mice. At the active lesion, we found monocyte chemotactic, proinflammatory, and immunoregulatory cytokines. The level was enhanced in immunized mice challenged with TDM. This result implies that both nonimmune and immune mechanisms participate in granulomatous inflammation induced by mycobacterial infection. Taken together with a previous report, this study shows that TDM is a pleiotropic molecule against the host and plays an important role in the pathogenesis of tuberculosis.The pathogenesis of tuberculosis is a function of the pathogen, Mycobacterium tuberculosis, and of the immune response of the host to the pathogen (5, 14). Tuberculosis is a chronic infection with M. tuberculosis complex, including M. tuberculosis and Mycobacterium bovis, that is characterized morphologically by granulomatous inflammation, a compact organized collection of macrophages and their derivatives, such as epithelioid and giant cells, at the site of infection (19). The pathogenicity of M. tuberculosis is related to its ability to escape killing by macrophages and induce delayed-type hypersensitivity (DTH) (5,14,19).Granulomatous inflammation can be broadly classified as either a hypersensitivity (immunologic, T-cell-dependent) type or a foreign-body (nonimmunologic, T-cell-independent) type (19,20). There is much known, but we still have a long way to go to understand the mechanism of M. tuberculosis pathogenicity. Mycobacteria are rich in lipids. Lipid components of the M. tuberculosis cell wall participate in pathogenesis. Cord factor (trehalose 6,6Ј-dimycolate [TDM]), a surface glycolipid, causes M. tuberculosis to grow in serpentine cords in vitro. Virulent strains of M. tuberculosis have TDM on their surface (2), and injection of purified TDM into experimental animals induces lesions characterized by chronic granulomatous inflammation (6,29).To clarify host responses to mycobacterial TDM, including immunogenicity and pathogenicity, we have analyzed the footpad reactions, histopathology, and cytokine profiles of experimental granulomatous lesions in immunized and unimmunized mic...

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Section: Discussionmentioning

confidence: 99%

Trehalose 6,6′-Dimycolate (Cord Factor) ofMycobacterium tuberculosisInduces Foreign-Body- and Hypersensitivity-Type Granulomas in Mice

Yamagami¹,

Matsumoto²,

Fujiwara³

et al. 2001

Infect Immun

101

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“…The reason for the secretion of higher amounts of IL-12 by M. avium-infected DC than by autologous M is unknown; however, data suggest a significant role for DC in the host defense against M. avium. Both in humans and in mice, IL-12 is required for resistance to M. avium (8,11,14,20,28). IL-12 augments cell-mediated immunity by stimulating production of gamma interferon and proliferation of T lymphocytes as well as of NK cells (9,15 Infection of DC with M. avium resulted in a significant increase in apoptotic death from 5 days after infection (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…IL-12 favors the development of CD4 ϩ T-helper 1 cells (38). In mice, endogenous IL-12 is required for resistance to M. avium infection (28), and administering recombinant IL-12 augmented resistance to M. avium infection in susceptible mice (11,20). In keeping with these findings, the adherent cells from patients with familial disseminated M. avium complex infection were shown to have a defect in IL-12 production (14).…”

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confidence: 99%

Interaction ofMycobacterium aviumwith Human Monocyte-Derived Dendritic Cells

et al. 2000

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The mechanism by which mycobacteria elicit class I-restricted T-cell responses remains undefined because these organisms have been shown to reside exclusively within membrane-bound vesicles in macrophages (M), their primary host cells. We studied the interaction of M. avium with dendritic cells (DC) because they are the most potent antigen-presenting cells and are abundant at M. avium infection sites. We observed that both DC and M, generated from human peripheral blood monocytes by short-term culture, internalized M. avium. The onset of programmed cell death and the percentage of apoptotic cells in infected DC and M were comparable. However, following infection, DC secreted significantly larger amounts of interleukin-12, but not interleukin-1␤, than infected autologous M. Further analysis of infected cells showed that while phagosomes failed to acidify in both M. avium-infected DC and M, bacilli grew more slowly in DC. Electron microscopy studies revealed that M. avium resided within endocytic vacuoles in both cell types. The vacuolar membrane surrounding some bacilli in approximately 10% of the vacuoles in DC possessed several breaks. The importance of this finding will have to be addressed in future studies.Organisms of the Mycobacterium avium complex are rarely pathogenic for healthy individuals (17) but cause disseminated disease in patients with AIDS (24, 40) and localized pulmonary infection in non-AIDS patients with underlying chronic lung disease (26). Infection with M. avium poses staggering public health problems because of the limited susceptibility of this organism to available antibiotics (12) and the ability of these bacilli to become resistant to commonly used antituberculosis agents (19). To develop new strategies for treating M. avium infection, we need to better understand the interactions of this organism with the host's immune system.As is the case with other mycobacteria, the importance of CD8 ϩ T cells in resistance to M. avium is controversial (6, 27) because the mechanism by which M. avium-derived molecules gain access to the cytoplasmic presentation pathway to elicit major histocompatibility complex class I-restricted T cells remains undefined. It is widely accepted that M. avium, a facultative intracellular bacillus, impedes macrophages' (M) processing and presentation of antigen by restricting vacuole maturation (10,36,39). In view of the paradox concerning the involvement of mycobacterium-specific major histocompatibility complex class I-restricted T cells in the control of infection and the finding that M. avium remains primarily within membrane-bound vesicles in M, we analyzed human dendritic cells (DC) infected in vitro with M. avium for uptake and intracellular growth of bacilli, apoptotic death, production of interleukin-12 (IL-12), fusigenicity of bacilli containing vacuoles with lysosomes, and the intracellular localization of the bacteria. The belief that M. avium may display behavior in DC different from its behavior in M was inspired by studies showing that in DC there is a...

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“…Exogenous IL-12 has been shown to promote the clearance of Mycobacterium avium in murine models of infection (10,24,45). IL-12 may be useful for HIV therapy or its complications (6,21,22) and was used successfully in a patient with refractory extrapulmonary TB after an initial failure with antituberculous drugs and IFN-␥ (17).…”

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confidence: 99%

Interleukin-12 Therapy Reduces the Number of Immune Cells and Pathology in Lungs of Mice Infected withMycobacterium tuberculosis

Nolt

Flynn

2004

Infect Immun

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Interleukin (IL)-12 Deficiency in Susceptible Mice Infected with Mycobacterium avium and Amelioration of Established Infection by IL-12 Replacement Therapy

Cited by 32 publications

References 47 publications

Trehalose 6,6′-Dimycolate (Cord Factor) ofMycobacterium tuberculosisInduces Foreign-Body- and Hypersensitivity-Type Granulomas in Mice

Trehalose 6,6′-Dimycolate (Cord Factor) ofMycobacterium tuberculosisInduces Foreign-Body- and Hypersensitivity-Type Granulomas in Mice

Interaction ofMycobacterium aviumwith Human Monocyte-Derived Dendritic Cells

Interleukin-12 Therapy Reduces the Number of Immune Cells and Pathology in Lungs of Mice Infected withMycobacterium tuberculosis

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