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

Abstract

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.

In Vivo IL-10 Production Reactivates Chronic Pulmonary Tuberculosis in C57BL/6 Mice

“…In a mouse model of progressive primary tuberculosis, IL-10 was not detected until at least 6 mo (180 days) following an infection with M. tuberculosis (29), and we demonstrate in this study that the C57BL/6 mouse strain produced very little IL-10 during chronic M. tuberculosis infection. These results suggest that the production of IL-10 is not associated with the initial control of infection, but that this cytokine may be more important during the chronic or latent phase of tuberculosis in this model.…”

The Inflammatory Response in Mycobacterium Tuberculosis Infection

“…Interestingly, the peak numbers of PMN appeared about a week before the peak levels of lymphocytes (Fulton et al, 2000). Also, cytokine expression in situ is characterized by excess pro-inflammatory molecules (Howard and Zwilling, 1998;Mustafa et al, 2000). On the other band, data from limited studies of human primary infection indicate that, among the household contacts of smear-positive TB patients, the majority experience granulocytosis, and produce excess TNF-a, and have a higher frequency of IFN-y-producing cells in response to MTB antigens in their broncho-alveolar lavage (BAL) fluid (Schwander et al, 2000).…”

TB Research at UT-Houston – A review of cord factor: new approaches to drugs, vaccines and the pathogenesis of tuberculosis

“…19,62 In murine studies, mycobacterial components have been shown to accumulate with host lipids. 63 Our hypothesis is that conditions eventually develop for activating the toxicity of the TDM by interaction with lipid droplets. Once activated, the toxicity of TDM increases several orders of magnitude and it becomes highly immunogenic leading to the rapid necrosis and cavity formation.…”