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Chapter 3 : Granuloma Formation in Mouse and Guinea Pig Models of Experimental Tuberculosis

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Granuloma Formation in Mouse and Guinea Pig Models of Experimental Tuberculosis, Page 1 of 2

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Abstract:

The mouse and guinea pig models of experimental tuberculosis are important and widely used for the practical purpose of screening new drugs and vaccines. An advantage of the mouse model is that a huge array of immunological reagents are available, but there are obvious differences in the immunopathologies of the disease after low-dose aerosol administration with compared with human disease. This chapter highlights and compares the primary facets of the granulomatous process in the mouse and guinea pig models of aerosol-induced experimental tuberculosis. It discusses how these processes reflect the underlying immune response, with the caveat that this process remains relatively poorly understood. The guinea pig is an important animal model of tuberculosis, including the development of what is regarded as the "classical granuloma". Damage to blood vessels, indicated by the observable fibrin deposition, would prevent recognition of adhesion/integrin molecules by lymphocytes and prevent their movement into the lesions. The CD4 and CD8 responses are described in the mouse and the guinea pig, with CD4 cells forming large aggregations dominating the granulomas and with CD8 cells more sparse and distributed more toward the periphery of the granuloma.

Citation: Turner O, Basaraba R, Frank A, Orme I. 2003. Granuloma Formation in Mouse and Guinea Pig Models of Experimental Tuberculosis, p 65-84. In Boros D (ed), Granulomatous Infections and Inflammations. ASM Press, Washington, DC. doi: 10.1128/9781555817879.ch3

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Image of Figure 1
Figure 1

Representative photomicrographs of lung from C57BL/6 mice at multiple time points after aerosol infection with (A) 3 days postinfection. Note the clear, open terminal airways and alveoli. Thin septae are punctuated by the nuclei of type I and II pneumocytes, endothelial cells, and alveolar macrophages. Normal respiratory epithelium lines the terminal bronchiole (arrow). Loose collagenous connective tissue separates airway from artery. (B) 16 days postinfection. Alveolar septae are expanded by lymphocytes, congested blood vessels, and mild edema. Alveolar macrophages are more prominent, and lymphocytes can be seen in the interstitium between artery and terminal bronchiole. (C) 30 days postinfection. Perivascular and peribronchial lymphoid cuffs and epithelioid macrophages are a common feature, and they extend into the surrounding parenchyma and expand the alveolar septae. (D) 60 days postinfection. Perivascular and peribronchial lymphoid cuffing is prominent, and the alveoli between them are filled with epithelioid and large foamy macrophages. (E) 150 days postinfection. Numerous lymphocytes extend into and surround macrophage-filled alveoli. (F) 250 days postinfection. Tight lymphocytic aggregates are surrounded by foamy macrophages with multifocal necrosis. Cholesterol clefts are prominent (arrow). In all figures, bar = 10 m, = bronchiole, = terminal bronchiole, = arteriole. All sections are stained with hematoxylin and eosin.

Citation: Turner O, Basaraba R, Frank A, Orme I. 2003. Granuloma Formation in Mouse and Guinea Pig Models of Experimental Tuberculosis, p 65-84. In Boros D (ed), Granulomatous Infections and Inflammations. ASM Press, Washington, DC. doi: 10.1128/9781555817879.ch3
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Image of Figure 2
Figure 2

Representative photomicrographs of lung from C57BL/6 mice at 304 days after aerosol infection with (A) Multinucleate giant cell (arrow). (B) Pockets of neutrophils (arrows). (C) High magnification of area in black box in B. Note multiple plasma cells (arrow). In all figures, bar=10 m. All sections are stained with hematoxylin and eosin.

Citation: Turner O, Basaraba R, Frank A, Orme I. 2003. Granuloma Formation in Mouse and Guinea Pig Models of Experimental Tuberculosis, p 65-84. In Boros D (ed), Granulomatous Infections and Inflammations. ASM Press, Washington, DC. doi: 10.1128/9781555817879.ch3
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Image of Figure 3
Figure 3

Representative photomicrographs of immunohistochemical staining for (A) CD4 lymphocytes and (B) CD8 cells in 5-μm serial sections of lung from C57BL/6 mice at 30 days after aerosol infection with Bar = 100 μm.

Citation: Turner O, Basaraba R, Frank A, Orme I. 2003. Granuloma Formation in Mouse and Guinea Pig Models of Experimental Tuberculosis, p 65-84. In Boros D (ed), Granulomatous Infections and Inflammations. ASM Press, Washington, DC. doi: 10.1128/9781555817879.ch3
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Image of Figure 4
Figure 4

Schematic of classic granuloma with central necrotic core surrounded by concentric layers of macrophages and lymphocytes enclosed by fibrosis.

Citation: Turner O, Basaraba R, Frank A, Orme I. 2003. Granuloma Formation in Mouse and Guinea Pig Models of Experimental Tuberculosis, p 65-84. In Boros D (ed), Granulomatous Infections and Inflammations. ASM Press, Washington, DC. doi: 10.1128/9781555817879.ch3
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Image of Figure 5
Figure 5

Representative photomicrographs of the four stages of pulmonary granuloma development in the guinea pig after aerosol infection with (A) Stage 1 granuloma. Single discrete round focus of macrophages admixed with granulocytes and small numbers of lymphocytes adjacent to a large blood vessel and airway; = artery, = bronchiole, = cartilage, bar = 100 μm. (B) Stage 1 granuloma. High magnification of the area delineated by black rectangle in panel A is shown. Note the abundance of granulocytes (arrows) intermixed with epithelioid macrophages and the lack of normal alveolar structure. Bar = 10 m. (C) Stage 2 granuloma. Single discrete round focus of macrophages with an eosinophilic, necrotic core () abutting a bronchiole (). Bar=100 μm. (D) Stage 2 granuloma. High magnification of the area delineated by black rectangle in panel C is shown. Note the abundance of granulocytes (arrows) intermixed with epithelioid macrophages and lymphocytes. Karyorrhectic debris is present in and around the core (), and there are multiple small scattered islands of fibrin (*). Bar = 10 μm. (E) Stage 3 granuloma. A discrete round lesion with a distinct necrotic core () is surrounded by a layer of epithelioid and foamy macrophages. This is in turn surrounded by a prominent darkly staining layer of lymphocytes (*), which are admixed with further macrophages at the extreme margins of the lesion. A bronchiole () is present at one margin. Bar = 100 μm. (F) Stage 3 granuloma; higher magnification of area delineated by black rectangle in E. Note the karyorrhectic debris in and around the core area to the right (), the dense sheet of epithelioid and foamy macrophages infiltrated by granulocytes surrounding it, and (on the left side) a region rich in lymphocytes, in between which there is considerable collagen deposition (arrow) beyond this. Bar = 10 μm. (G) Stage 4 granuloma. The core () has become mineralized and fractured. Epithelioid and foamy macrophages admixed with lymphocytes surround it, enveloped in an elaborate network of fibrosis (). A medium-sized artery () and bronchiole () are present at the margins. Bar =100 μm. (H) Stage 4 granuloma; area of lesion showing longitudinal section of a bronchiole (), which is blocked with granulocytic and necrotic debris (arrows) filling the lumen. Dense sheets of macrophages with scattered lymphocytes and interweaving fibrosis () surround the airway. Bar = 100 μm. All sections are stained with hematoxylin and eosin.

Citation: Turner O, Basaraba R, Frank A, Orme I. 2003. Granuloma Formation in Mouse and Guinea Pig Models of Experimental Tuberculosis, p 65-84. In Boros D (ed), Granulomatous Infections and Inflammations. ASM Press, Washington, DC. doi: 10.1128/9781555817879.ch3
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Image of Figure 6
Figure 6

Representative photomicrograph of stage 4 pulmonary granuloma in the guinea pig after aerosol infection with The core () has become mineralized and fractured. Epithelioid and foamy macrophages admixed with lymphocytes surround it, all enveloped in an elaborate network of fibrosis (). A bronchiole lumen () is blocked with granulocytic and necrotic debris. Bar = 100 μm. All sections are stained with hematoxylin and eosin.

Citation: Turner O, Basaraba R, Frank A, Orme I. 2003. Granuloma Formation in Mouse and Guinea Pig Models of Experimental Tuberculosis, p 65-84. In Boros D (ed), Granulomatous Infections and Inflammations. ASM Press, Washington, DC. doi: 10.1128/9781555817879.ch3
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