A Mouse Model for Slowly Progressive Primary Tuberculosis

Mustafa, Tehmina; Phyu, Sabai; Nilsen, Rune; Jönsson, Roland; Bjune, Gunnar

doi:10.1046/j.1365-3083.1999.00596.x

Cited by 52 publications

(86 citation statements)

References 30 publications

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“…During the course of slowly progressive TB, mycobacterial antigens were detected in only 3±6% of the Mf in the lesions, as has been described previously [17]. Neighbouring sections stained for TNF-a, mycobacterial antigens and IL-10 were analysed during phase 3.…”

Section: Resultsmentioning

confidence: 68%

“…During phase 2 the mice start to show signs of illness [17]. The host immunity controlled bacillary multiplication and pathology.…”

Section: Resultsmentioning

confidence: 99%

“…All the antibodies used are described in Table 1. The sections were stained by using the avidin±biotin±peroxidase complex (ABC; Dako A/S, Glostrup, Denmark), as described previously [17]. Brie¯y, the sections were ®xed in cold acetone for 10 min.…”

Section: Methodsmentioning

confidence: 99%

“…We have previously established a mouse model of slowly progressive primary tuberculosis [17,18]. Mice infected intraperitoneally (i.p.)…”

Section: Introductionmentioning

confidence: 99%

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In Situ Expression of Cytokines and Cellular Phenotypes in the Lungs of Mice with Slowly Progressive Primary Tuberculosis

Mustafa

Phyu²,

Nilsen³

et al. 2000

Scand J Immunol

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51:548±556The cellular phenotypes and the expression of cytokines were studied in the lungs of mice, using immunohistochemistry, during different phases of slowly progressive primary murine tuberculosis infection. During the ®rst phase the small focal lesions in healthy mice contained predominantly interleukin-2 (IL-2)-expressing cells. A small number of tumour necrosis factor-a (TNF-a)-, monocyte chemoattractant protein-1 (MCP-1)-and IL-10-expressing cells were also present. IL-4-expressing cells were not detected. During the second phase the mice became unwell, but the bacterial counts and the size of focal lesions stabilized. IL-4-expressing cells appeared. The IL-10-, TNF-a-and MCP-1-expressing cells increased in number. On progression to phase three, the mice became seriously unwell and died rapidly. The in¯ammation spread to < 80% of the lung parenchyma. There was a marked increase in the number of IL-10-expressing cells. Expression of other cytokines was similar to that observed in the second phase. In the lesions, 3±6% of the macrophages (Mf) containing mycobacterial antigens expressed high levels of IL-10 and TNF-a. The absolute numbers of CD3-, CD4-and CD11b-expressing cells in the lesions increased with the progression of infection. The numbers of CD8 cells were reduced in the last phase of infection. The kinetics of T-lymphocyte subsets and the pattern of cytokine expression changed with the type and degree of tissue injury. The small number of Mf with a heavy load of mycobacterial antigens may be the cause of this disturbance in cytokine balance, thus leading to progression of in¯ammation.

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Section: Resultsmentioning

confidence: 68%

“…During phase 2 the mice start to show signs of illness [17]. The host immunity controlled bacillary multiplication and pathology.…”

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…We have previously established a mouse model of slowly progressive primary tuberculosis [17,18]. Mice infected intraperitoneally (i.p.)…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

In Situ Expression of Cytokines and Cellular Phenotypes in the Lungs of Mice with Slowly Progressive Primary Tuberculosis

Mustafa

Phyu²,

Nilsen³

et al. 2000

Scand J Immunol

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show abstract

“…Recently, animal models for latent tuberculosis (LTB) and slowly progressive primary tuberculosis (SPTB) have been developed and the results show that the two disease models closely mimic human LTB and SPTB [17,18]. However, cytokine profiles, in particular those of IL-15 during LTB and SPTB, have not been well documented.…”

Section: Introductionmentioning

confidence: 99%

Cytokine profile during latent and slowly progressive primary tuberculosis: a possible role for interleukin-15 in mediating clinical disease

Abebe

Mustafa

Nerland

et al. 2005

Clinical and Experimental Immunology

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SummaryRecently, mouse models for latent (LTB) and slowly progressive primary tuberculosis (SPTB) have been established. However, cytokine profiles during the two models are not well established. Using quantitative reverse transcriptionpolymerase chain reaction (qRT-PCR) we studied the expression levels of interleukin (IL)-2, IL-4, IL-10, IL-12, IL-15, interferon (IFN)-γ γ γ γ and tumour necrosis factor (TNF)-α α α α during the course of LTB and SPTB in the lungs and spleens of B6D2F1Bom mice infected with the H37Rv strain of Mycobacterium tuberculosis ( Mtb ). The results show that, except for IL-4, cytokine expression levels were significantly higher during SPTB than LTB in both the lungs and spleens. During LTB, all the cytokines (except IL-2 in the lungs) had higher expression levels during the initial period of infection both in the lungs and spleens. During SPTB, the expression levels of IL-15 increased significantly from phases 1 to 3 in the lungs. The expression levels of IL-10, IL-12 and IFN-γ γ γ γ increased significantly from 2 to 3 in the lungs. IL-10 and IL-15 increased significantly from phases 2 to 3, whereas that of TNF-α α α α decreased significantly and progressively from phases 1 to 3 in the spleens. Over-expression of proinflammatory cytokines during active disease has been well documented, but factor(s) underlying such over-expression is not known. In the present study, there was a progressive and significant increase in the expression levels of IL-15, together with Th1 cytokines (IL-12 and IFN-γ γ γ γ ) during SPTB but a significant decrease during LTB. IL-15 is known to up-regulate the production of proinflammatory cytokines, IL-1β β β β , IL-8, IL-12, IL-17, IFN-γ γ γ γ and TNF-α α α α and has an inhibitory effect on activation-induced cell death. IL-15 is known to be involved in many proinflammatory disease states such as rheumatoid arthritis, sarcoidosis, inflammatory bowel diseases, autoimmune diabetes, etc. Our results, together with the above observations, suggest that IL-15 may play an important role in mediating active disease during Mtb infection.

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Detecting and characterizing cellular responses to Mycobacterium tuberculosis from histology slides

2013

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Infection with Mycobacterium tuberculosis (M.tb) results in immune cell recruitment to the lungs, forming macrophage-rich regions (granulomas) and lymphocyte-rich regions (lymphocytic cuffs). The objective of this study was to accurately identify and characterize these regions from hematoxylin and eosin (H&E)-stained tissue slides. The two target regions (granulomas and lymphocytic cuffs) can be identified by their morphological characteristics. Their most differentiating characteristic on H&E slides is cell density. We developed a computational framework, called DeHiDe, to detect and classify high cell-density regions in histology slides. DeHiDe employed a novel internuclei geodesic distance calculation and Dulmange Mendelsohn permutation to detect and classify high cell-density regions. Lung tissue slides of mice experimentally infected with M.tb were stained with H&E and digitized. A total of 21 digital slides were used to develop and train the computational framework. The performance of the framework was evaluated using two main outcome measures: correct detection of potential regions, and correct classification of potential regions into granulomas and lymphocytic cuffs. DeHiDe provided a detection accuracy of 99.39% while it correctly classified 90.87% of the detected regions for the images where the expert pathologist produced the same ground truth during the first and second round of annotations. We showed that DeHiDe could detect high cell-density regions in a heterogeneous cell environment with non-convex tissue shapes.

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A Mouse Model for Slowly Progressive Primary Tuberculosis

Cited by 52 publications

References 30 publications

In Situ Expression of Cytokines and Cellular Phenotypes in the Lungs of Mice with Slowly Progressive Primary Tuberculosis

In Situ Expression of Cytokines and Cellular Phenotypes in the Lungs of Mice with Slowly Progressive Primary Tuberculosis

Cytokine profile during latent and slowly progressive primary tuberculosis: a possible role for interleukin-15 in mediating clinical disease

Detecting and characterizing cellular responses to Mycobacterium tuberculosis from histology slides

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