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Chapter 23 : Characteristics of Rabbit BCG Lesions and Efficacies of BCG and Mycobacterium microti Vaccines
Author:
Arthur M. Dannenberg, Jr.1
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Affiliations:
1: Center for Tuberculosis Research Departments of Environmental Health Sciences, Molecular Microbiology and Immunology, and Epidemiology, Bloomberg School of Public Health Department of Pathology, School of Medicine Johns Hopkins University, Baltimore, Maryland 21205
Content Type: Monograph
Publication Year:
2006
Category: Clinical Microbiology; Bacterial Pathogenesis
Book DOI:
10.1128/9781555815684
Chapter DOI:
10.1128/9781555815684.ch23
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Abstract:
In rabbits (and humans), dermal BCG lesions have the same components as lesions caused by virulent tubercle bacilli, i.e., a caseous liquefied center surrounded by tuberculous granulation tissue. Therefore, BCG lesions can be used as a model in which to study the host response to this disease. In immunocompetent hosts, BCG lesions do not progress and always heal. The rate of healing of dermal BCG lesions reflected the native and acquired resistance of Lurie’s susceptible and resistant inbred rabbit strains. Similarly, the rate of healing of BCG lesions has been shown to reflect the resistance to tuberculosis of human populations. However, the healing of BCG lesions in individual rabbits and humans may vary considerably from the mean. In Lurie’s natively resistant rabbits, immunization with BCG was quite effective in preventing many grossly visible primary pulmonary tubercles. In his natively susceptible rabbits, BCG was hardly effective at all. In other words, the rabbits that needed it the least were helped by BCG vaccination the most, and the rabbits that needed it the most were helped the least. This principle also applies to human populations: persons with poor resistance to clinical tuberculosis would develop less immunity from BCG administration than persons with strong resistance. The efficacies of various BCG and Mycobacterium microti (the vole bacillus) vaccines were evaluated in commercial outbred rabbits by the tubercle-count method. Both of these vaccine types were effective. Recombinant BCG vaccines that contain additional antigenic components may be more promising than currently used BCG vaccines.
Citation:
Dannenberg, Jr. A.
2006.
Characteristics of Rabbit BCG Lesions and Efficacies of BCG and Mycobacterium microti Vaccines,
p 354-364.
In
Pathogenesis of Human Pulmonary Tuberculosis.
ASM Press, Washington, DC.
doi: 10.1128/9781555815684.ch23
Figures
Characteristics of Rabbit BCG Lesions and Efficacies of BCG and Mycobacterium microti Vaccines
Citation:
Dannenberg, Jr. A.
2006.
Characteristics of Rabbit BCG Lesions and Efficacies of BCG and Mycobacterium microti Vaccines,
p 354-364.
In
Pathogenesis of Human Pulmonary Tuberculosis.
ASM Press, Washington, DC.
doi: 10.1128/9781555815684.ch23
/content/10.1128/9781555815684.ch23.ch23fig01
FIGURE 1
Size of BCG lesions in rabbits at various times after receiving 8 intradermal injections of about 5 × 106 BCG bacilli on each flank (3). The biphasic nature of the curve is due to a decline in the initial nonspecific inflammatory response to the vaccine followed by the development of an antigen-specific response. The size of 2-day tuberculin reactions in these rabbits is shown below the curve: − = 0 to 100 mm3, + = 100 to 200 mm3, ++ = 200 to 400 mm3, and +++ = greater than 400 mm3. The rabbits had significant tuberculin reactions from 9 days on. The means and their standard errors are shown along with the statistical significance between adjacent points: *P < 0.05 and ***P < 0.01. Reproduced with permission from reference 3.
10.1128/9781555815684/f0355-01_thmb.gif
10.1128/9781555815684/f0355-01.gif
FIGURE 1
Size of BCG lesions in rabbits at various times after receiving 8 intradermal injections of about 5 × 106 BCG bacilli on each flank (3). The biphasic nature of the curve is due to a decline in the initial nonspecific inflammatory response to the vaccine followed by the development of an antigen-specific response. The size of 2-day tuberculin reactions in these rabbits is shown below the curve: − = 0 to 100 mm3, + = 100 to 200 mm3, ++ = 200 to 400 mm3, and +++ = greater than 400 mm3. The rabbits had significant tuberculin reactions from 9 days on. The means and their standard errors are shown along with the statistical significance between adjacent points: *P < 0.05 and ***P < 0.01. Reproduced with permission from reference 3.
Citation:
Dannenberg, Jr. A.
2006.
Characteristics of Rabbit BCG Lesions and Efficacies of BCG and Mycobacterium microti Vaccines,
p 354-364.
In
Pathogenesis of Human Pulmonary Tuberculosis.
ASM Press, Washington, DC.
doi: 10.1128/9781555815684.ch23
/content/10.1128/9781555815684.ch23.ch23fig02
FIGURE 2
Mononuclear cells (MN) and granulocytes (PMN) per mm2 of tissue section in rabbit BCG lesions at various times during their development and healing. PMN accumulated around the caseous necrotic areas. Note that, although the number of MN per mm2 remained high during healing (at 37 days), the volumes of the BCG lesions were diminished (see Fig. 1).***
P < 0.01. Reproduced with permission from reference 3.
10.1128/9781555815684/f0356-01_thmb.gif
10.1128/9781555815684/f0356-01.gif
FIGURE 2
Mononuclear cells (MN) and granulocytes (PMN) per mm2 of tissue section in rabbit BCG lesions at various times during their development and healing. PMN accumulated around the caseous necrotic areas. Note that, although the number of MN per mm2 remained high during healing (at 37 days), the volumes of the BCG lesions were diminished (see Fig. 1).*** P < 0.01. Reproduced with permission from reference 3.
Citation:
Dannenberg, Jr. A.
2006.
Characteristics of Rabbit BCG Lesions and Efficacies of BCG and Mycobacterium microti Vaccines,
p 354-364.
In
Pathogenesis of Human Pulmonary Tuberculosis.
ASM Press, Washington, DC.
doi: 10.1128/9781555815684.ch23
/content/10.1128/9781555815684.ch23.ch23fig03
FIGURE 3
Number of bacilli in central areas of rabbit BCG lesions of various ages, visualized by acid-fast staining with carbol-fuchsin. As the lesions progressed, a shift occurred from bacilli located intracellularly (mostly in intact and necrotic macrophages) to bacilli located extracellularly in areas of (liquefied) caseous necrosis. By 23 days, the number of bacilli was greatly reduced. Reproduced with permission from reference 3.
10.1128/9781555815684/f0357-01_thmb.gif
10.1128/9781555815684/f0357-01.gif
FIGURE 3
Number of bacilli in central areas of rabbit BCG lesions of various ages, visualized by acid-fast staining with carbol-fuchsin. As the lesions progressed, a shift occurred from bacilli located intracellularly (mostly in intact and necrotic macrophages) to bacilli located extracellularly in areas of (liquefied) caseous necrosis. By 23 days, the number of bacilli was greatly reduced. Reproduced with permission from reference 3.
Citation:
Dannenberg, Jr. A.
2006.
Characteristics of Rabbit BCG Lesions and Efficacies of BCG and Mycobacterium microti Vaccines,
p 354-364.
In
Pathogenesis of Human Pulmonary Tuberculosis.
ASM Press, Washington, DC.
doi: 10.1128/9781555815684.ch23
/content/10.1128/9781555815684.ch23.ch23fig04
FIGURE 4
Liquefied caseous center of a 5-day dermal BCG lesion stained for tubercle bacilli. Many bacilli appear as clumps within darkly stained macrophages. Other bacilli are located extracellularly in the liquefied debris. All darkly stained tiny particles are bacilli. Since this is necrotic material, the macrophages are not distinctly recognizable in the photograph, but their rounded outline and size clearly identify their cell type. Fixed-frozen tissue sections stained by carbol-fuchsin and counterstained with methylene blue. Magnification, ×800. Reproduced with permission from reference 3.
10.1128/9781555815684/f0358-01_thmb.gif
10.1128/9781555815684/f0358-01.gif
FIGURE 4
Liquefied caseous center of a 5-day dermal BCG lesion stained for tubercle bacilli. Many bacilli appear as clumps within darkly stained macrophages. Other bacilli are located extracellularly in the liquefied debris. All darkly stained tiny particles are bacilli. Since this is necrotic material, the macrophages are not distinctly recognizable in the photograph, but their rounded outline and size clearly identify their cell type. Fixed-frozen tissue sections stained by carbol-fuchsin and counterstained with methylene blue. Magnification, ×800. Reproduced with permission from reference 3.
Citation:
Dannenberg, Jr. A.
2006.
Characteristics of Rabbit BCG Lesions and Efficacies of BCG and Mycobacterium microti Vaccines,
p 354-364.
In
Pathogenesis of Human Pulmonary Tuberculosis.
ASM Press, Washington, DC.
doi: 10.1128/9781555815684.ch23
/content/10.1128/9781555815684.ch23.ch23fig05
FIGURE 5
Size of dermal BCG lesions and tuberculin reactions in Lurie’s inbred resistant and susceptible rabbits at various times after infection. Note that at 1 and 2 weeks, the BCG lesions (A) were largest in resistant strain III rabbits, because their tuberculin sensitivity (B) developed more quickly and to a greater degree. Then, the BCG lesions in this resistant strain III declined rapidly and healed sooner than did those in the susceptible strain C. Strain A rabbits were of intermediate resistance when this experiment was performed. Reproduced with permission from reference 11.
10.1128/9781555815684/f0360-01_thmb.gif
10.1128/9781555815684/f0360-01.gif
FIGURE 5
Size of dermal BCG lesions and tuberculin reactions in Lurie’s inbred resistant and susceptible rabbits at various times after infection. Note that at 1 and 2 weeks, the BCG lesions (A) were largest in resistant strain III rabbits, because their tuberculin sensitivity (B) developed more quickly and to a greater degree. Then, the BCG lesions in this resistant strain III declined rapidly and healed sooner than did those in the susceptible strain C. Strain A rabbits were of intermediate resistance when this experiment was performed. Reproduced with permission from reference 11.
Citation:
Dannenberg, Jr. A.
2006.
Characteristics of Rabbit BCG Lesions and Efficacies of BCG and Mycobacterium microti Vaccines,
p 354-364.
In
Pathogenesis of Human Pulmonary Tuberculosis.
ASM Press, Washington, DC.
doi: 10.1128/9781555815684.ch23
/content/10.1128/9781555815684.ch23.ch23fig06
FIGURE 6
Antibody titers in inbred resistant strain III rabbits and susceptible strain FC rabbits at various times after an intradermal injection of BCG. The antibodies were determined by the hemagglutination method of Middlebrook (31) with Old Tuberculin as the antigen. Note that such antibodies reached much higher titers in the resistant group. Adapted from reference 11. The FC strain rabbits were similar to the C strain rabbits in their resistance to tuberculosis (see chapter 14).
10.1128/9781555815684/f0361-01_thmb.gif
10.1128/9781555815684/f0361-01.gif
FIGURE 6
Antibody titers in inbred resistant strain III rabbits and susceptible strain FC rabbits at various times after an intradermal injection of BCG. The antibodies were determined by the hemagglutination method of Middlebrook (31) with Old Tuberculin as the antigen. Note that such antibodies reached much higher titers in the resistant group. Adapted from reference 11. The FC strain rabbits were similar to the C strain rabbits in their resistance to tuberculosis (see chapter 14).
Citation:
Dannenberg, Jr. A.
2006.
Characteristics of Rabbit BCG Lesions and Efficacies of BCG and Mycobacterium microti Vaccines,
p 354-364.
In
Pathogenesis of Human Pulmonary Tuberculosis.
ASM Press, Washington, DC.
doi: 10.1128/9781555815684.ch23
References
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Suga, M.,, A. M. Dannenberg, Jr., and, S. Higuchi. 1980. Macrophage functional heterogeneity in vivo: macrolocal and microlocal macrophage activation, identified by double-staining tissue sections of BCG granulomas for pairs of enzymes. Am. J. Pathol. 99: 305– 324.
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Nathan, C. F. 1987. Secretory products of macrophages. J. Clin. Investig. 79: 319– 326.
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Lurie, M. B.,, P. Zappasodi,, E. Cardona-Lynch, and, A. M. Dannenberg, Jr. 1952. The response to the intracutaneous inoculation of BCG as an index of native resistance to tuberculosis. J. Immunol. 68: 369– 387.
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Tables
Characteristics of Rabbit BCG Lesions and Efficacies of BCG and Mycobacterium microti Vaccines
Citation:
Dannenberg, Jr. A.
2006.
Characteristics of Rabbit BCG Lesions and Efficacies of BCG and Mycobacterium microti Vaccines,
p 354-364.
In
Pathogenesis of Human Pulmonary Tuberculosis.
ASM Press, Washington, DC.
doi: 10.1128/9781555815684.ch23
/content/10.1128/9781555815684.ch23.ch23tab01
TABLE 1
CD4 and CD8 cells in mononuclear cell populations within primary BCG lesions during their development and healing
a
TABLE 1
CD4 and CD8 cells in mononuclear cell populations within primary BCG lesions during their development and healing a
Citation:
Dannenberg, Jr. A.
2006.
Characteristics of Rabbit BCG Lesions and Efficacies of BCG and Mycobacterium microti Vaccines,
p 354-364.
In
Pathogenesis of Human Pulmonary Tuberculosis.
ASM Press, Washington, DC.
doi: 10.1128/9781555815684.ch23
/content/10.1128/9781555815684.ch23.ch23tab02
TABLE 2
Relative numbers of tubercle bacilli in dermal BCG lesions of resistant strain III rabbits and susceptible strain C rabbits at various times after infection
a
TABLE 2
Relative numbers of tubercle bacilli in dermal BCG lesions of resistant strain III rabbits and susceptible strain C rabbits at various times after infection a
Citation:
Dannenberg, Jr. A.
2006.
Characteristics of Rabbit BCG Lesions and Efficacies of BCG and Mycobacterium microti Vaccines,
p 354-364.
In
Pathogenesis of Human Pulmonary Tuberculosis.
ASM Press, Washington, DC.
doi: 10.1128/9781555815684.ch23
/content/10.1128/9781555815684.ch23.ch23tab03
TABLE 3
Number of inhaled human-type tubercle bacilli producing one grossly visible primary pulmonary tubercle in unvaccinated and BCG-vaccinated inbred resistant and susceptible rabbits (“the ratio” by the Lurie method)
a
TABLE 3
Number of inhaled human-type tubercle bacilli producing one grossly visible primary pulmonary tubercle in unvaccinated and BCG-vaccinated inbred resistant and susceptible rabbits (“the ratio” by the Lurie method) a
Citation:
Dannenberg, Jr. A.
2006.
Characteristics of Rabbit BCG Lesions and Efficacies of BCG and Mycobacterium microti Vaccines,
p 354-364.
In
Pathogenesis of Human Pulmonary Tuberculosis.
ASM Press, Washington, DC.
doi: 10.1128/9781555815684.ch23
/content/10.1128/9781555815684.ch23.ch23tab04
TABLE 4
Vaccine efficacy: number of grossly visible tubercles in vaccinated rabbits and their diameters as percentages of those found in controls
a
TABLE 4
Vaccine efficacy: number of grossly visible tubercles in vaccinated rabbits and their diameters as percentages of those found in controls a
Citation:
Dannenberg, Jr. A.
2006.
Characteristics of Rabbit BCG Lesions and Efficacies of BCG and Mycobacterium microti Vaccines,
p 354-364.
In
Pathogenesis of Human Pulmonary Tuberculosis.
ASM Press, Washington, DC.
doi: 10.1128/9781555815684.ch23