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The relative importance of T cell subsets in immunity and immunopathology of airborne Mycobacterium tuberculosis infection in mice.

Mogues T, Goodrich ME, Ryan L, LaCourse R, North RJ - J. Exp. Med. (2001)

Bottom Line: This was associated with the development of a macrophage-dominated alveolitis at sites of infection, with increased synthesis of IFN-gamma and NOS2 mRNA, and with an median survival time (MST) of 258.5 d.In the absence of CD4-mediated immunity (class II(-/-) mice), progressive bacterial growth continued in the lungs and in other organs beyond day 20, resulting in an MST of 77 d.By contrast, in the absence of CD8 T cell-mediated immunity, lung infection was controlled at a 1 log higher stationary level that induced a similar histopathologic response to that of WT mice, and resulted in an MST of 232 d.

View Article: PubMed Central - PubMed

Affiliation: The Trudeau Institute, Saranac Lake, New York 12983, USA.

ABSTRACT
Wild-type (WT) and targeted-mutant mice incapable of making alphabeta T cells, gammadelta T cells, class I major histocompatibility complex (MHC), class II MHC, interferon (IFN)-gamma, or inducible nitric oxide synthase (NOS2), were infected with Mycobacterium tuberculosis (Mtb) by aerosol, and monitored over time for their ability to (a) control infection, (b) develop histopathology at sites of infection, and (c) survive. WT mice acquired the ability to control and to hold infection at a stationary level from day 20 on. This was associated with the development of a macrophage-dominated alveolitis at sites of infection, with increased synthesis of IFN-gamma and NOS2 mRNA, and with an median survival time (MST) of 258.5 d. In the absence of alphabeta T cells, Mtb grew progressively and rapidly to induce a necrotic, neutrophil-dominated lung pathology that killed mice with an MST of 48 d. In the absence of CD4-mediated immunity (class II(-/-) mice), progressive bacterial growth continued in the lungs and in other organs beyond day 20, resulting in an MST of 77 d. By contrast, in the absence of CD8 T cell-mediated immunity, lung infection was controlled at a 1 log higher stationary level that induced a similar histopathologic response to that of WT mice, and resulted in an MST of 232 d.

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Changes in the quantity of mRNA for IFN-γ and NOS2 against time of infection in the lungs of WT, class I−/−, and class II−/− mice as determined by RPA. IFN-γ and NOS2 mRNA was upregulated from day 20 of infection on in WT mice. Likewise, IFN-γ and NOS2 mRNA was present in the lungs of class I−/− mice from days 20 on. In the lungs of class II−/− mice, in contrast, upregulation of IFN-γ mRNA was not evident until day 30, and relatively low levels were produced thereafter. Appreciable amounts of NOS2 mRNA were made in the lungs of these mice, but not until after day 30. GAPDH, glyceraldehyde 3-phosphate dehydrogenase.
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Figure 7: Changes in the quantity of mRNA for IFN-γ and NOS2 against time of infection in the lungs of WT, class I−/−, and class II−/− mice as determined by RPA. IFN-γ and NOS2 mRNA was upregulated from day 20 of infection on in WT mice. Likewise, IFN-γ and NOS2 mRNA was present in the lungs of class I−/− mice from days 20 on. In the lungs of class II−/− mice, in contrast, upregulation of IFN-γ mRNA was not evident until day 30, and relatively low levels were produced thereafter. Appreciable amounts of NOS2 mRNA were made in the lungs of these mice, but not until after day 30. GAPDH, glyceraldehyde 3-phosphate dehydrogenase.

Mentions: According to the foregoing results, growth of Mtb in the lungs was maintained at a stationary level from day 20 on. It could be argued, therefore, that immunity would need to be continuously mediated and expressed in the lungs from day 20 on, as would be evidenced by the continuous synthesis of mRNA for IFN-γ and NOS2. This was investigated in WT and targeted mutant mice by multiprobe ribonuclease protection assay (RPA) analysis of RNA from lungs harvested at progressive stages of infection (Fig. 6 and Fig. 7). The results in Fig. 6 show that in the case of WT mice, NOS2 mRNA was constitutively synthesized in the lungs at low levels before infection was initiated, and that its synthesis was substantially upregulated from day 20 of infection on. IFN-γ mRNA was also synthesized in larger quantity in the lungs of WT mice from day 20 on, as was IL-4 mRNA, although in quantities too small to be visible in the figure. The presence of IL-4 mRNA was clearly visible in the original radioautograph. IL-10, IL-13, and IL-2 mRNAs were not detected in measurable quantities under the conditions of the assay. It will be noted (Fig. 6 and Fig. 7) that IL-15 mRNA was constitutively present in the lungs, and that its synthesis appeared not to be substantially altered in response to infection.


The relative importance of T cell subsets in immunity and immunopathology of airborne Mycobacterium tuberculosis infection in mice.

Mogues T, Goodrich ME, Ryan L, LaCourse R, North RJ - J. Exp. Med. (2001)

Changes in the quantity of mRNA for IFN-γ and NOS2 against time of infection in the lungs of WT, class I−/−, and class II−/− mice as determined by RPA. IFN-γ and NOS2 mRNA was upregulated from day 20 of infection on in WT mice. Likewise, IFN-γ and NOS2 mRNA was present in the lungs of class I−/− mice from days 20 on. In the lungs of class II−/− mice, in contrast, upregulation of IFN-γ mRNA was not evident until day 30, and relatively low levels were produced thereafter. Appreciable amounts of NOS2 mRNA were made in the lungs of these mice, but not until after day 30. GAPDH, glyceraldehyde 3-phosphate dehydrogenase.
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Related In: Results  -  Collection

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Figure 7: Changes in the quantity of mRNA for IFN-γ and NOS2 against time of infection in the lungs of WT, class I−/−, and class II−/− mice as determined by RPA. IFN-γ and NOS2 mRNA was upregulated from day 20 of infection on in WT mice. Likewise, IFN-γ and NOS2 mRNA was present in the lungs of class I−/− mice from days 20 on. In the lungs of class II−/− mice, in contrast, upregulation of IFN-γ mRNA was not evident until day 30, and relatively low levels were produced thereafter. Appreciable amounts of NOS2 mRNA were made in the lungs of these mice, but not until after day 30. GAPDH, glyceraldehyde 3-phosphate dehydrogenase.
Mentions: According to the foregoing results, growth of Mtb in the lungs was maintained at a stationary level from day 20 on. It could be argued, therefore, that immunity would need to be continuously mediated and expressed in the lungs from day 20 on, as would be evidenced by the continuous synthesis of mRNA for IFN-γ and NOS2. This was investigated in WT and targeted mutant mice by multiprobe ribonuclease protection assay (RPA) analysis of RNA from lungs harvested at progressive stages of infection (Fig. 6 and Fig. 7). The results in Fig. 6 show that in the case of WT mice, NOS2 mRNA was constitutively synthesized in the lungs at low levels before infection was initiated, and that its synthesis was substantially upregulated from day 20 of infection on. IFN-γ mRNA was also synthesized in larger quantity in the lungs of WT mice from day 20 on, as was IL-4 mRNA, although in quantities too small to be visible in the figure. The presence of IL-4 mRNA was clearly visible in the original radioautograph. IL-10, IL-13, and IL-2 mRNAs were not detected in measurable quantities under the conditions of the assay. It will be noted (Fig. 6 and Fig. 7) that IL-15 mRNA was constitutively present in the lungs, and that its synthesis appeared not to be substantially altered in response to infection.

Bottom Line: This was associated with the development of a macrophage-dominated alveolitis at sites of infection, with increased synthesis of IFN-gamma and NOS2 mRNA, and with an median survival time (MST) of 258.5 d.In the absence of CD4-mediated immunity (class II(-/-) mice), progressive bacterial growth continued in the lungs and in other organs beyond day 20, resulting in an MST of 77 d.By contrast, in the absence of CD8 T cell-mediated immunity, lung infection was controlled at a 1 log higher stationary level that induced a similar histopathologic response to that of WT mice, and resulted in an MST of 232 d.

View Article: PubMed Central - PubMed

Affiliation: The Trudeau Institute, Saranac Lake, New York 12983, USA.

ABSTRACT
Wild-type (WT) and targeted-mutant mice incapable of making alphabeta T cells, gammadelta T cells, class I major histocompatibility complex (MHC), class II MHC, interferon (IFN)-gamma, or inducible nitric oxide synthase (NOS2), were infected with Mycobacterium tuberculosis (Mtb) by aerosol, and monitored over time for their ability to (a) control infection, (b) develop histopathology at sites of infection, and (c) survive. WT mice acquired the ability to control and to hold infection at a stationary level from day 20 on. This was associated with the development of a macrophage-dominated alveolitis at sites of infection, with increased synthesis of IFN-gamma and NOS2 mRNA, and with an median survival time (MST) of 258.5 d. In the absence of alphabeta T cells, Mtb grew progressively and rapidly to induce a necrotic, neutrophil-dominated lung pathology that killed mice with an MST of 48 d. In the absence of CD4-mediated immunity (class II(-/-) mice), progressive bacterial growth continued in the lungs and in other organs beyond day 20, resulting in an MST of 77 d. By contrast, in the absence of CD8 T cell-mediated immunity, lung infection was controlled at a 1 log higher stationary level that induced a similar histopathologic response to that of WT mice, and resulted in an MST of 232 d.

Show MeSH
Related in: MedlinePlus