Tumor necrosis factor (TNF) plays a major role in the initial and long-term control of tuberculosis. The mechanisms by which this cytokine contributes to the control of Mycobacterium tuberculosis infection are numerous and therefore difficult to dissect. TNF is important in macrophage activation as well as cell recruitment to the site of infection. It is the primary signal important in granuloma formation, as neutralization of this cytokine leads to lack of control of initial or chronic infection, and loss of granuloma structure. In humans treated with TNF-neutralizing drugs, an increased susceptibility to tuberculosis, as well as other infectious diseases, is observed. We are using animal models to understand how TNF neutralization by these drugs can lead to reactivation of tuberculosis.
Tumor necrosis factor (TNF) plays an essential role in the immunologic maintenance of Mycobacterium tuberculosis infection. Although an increased rate of tuberculosis has been reported in humans treated with anti-TNF biological agents, disparate rates of disease have been observed between those treated with infliximab, an anti-TNF antibody, and etanercept, a TNF-neutralizing TNF receptor (TNFR) fusion molecule. We compared the effects of anti-TNF antibody and soluble TNFR fusion molecule in the murine model of tuberculosis. Systemic TNF neutralization was equivalent between these molecules, and both resulted in rapid morbidity at the initiation of infection. During chronic infection, administration of the receptor fusion molecule allowed the control of infection, whereas antibody treatment caused mice to die within a month. We provide evidence of decreased penetration into the granulomas by the receptor fusion molecule, compared with antibody. These findings begin to clarify the mechanistic difference between anti-TNF agents and their role in the exacerbation of tuberculosis.
The immune response to Mycobacterium tuberculosis (Mtb) infection is complex. Experimental evidence has revealed that tumor necrosis factor (TNF) plays a major role in host defense against Mtb in both active and latent phases of infection. TNF-neutralizing drugs used to treat inflammatory disorders have been reported to increase the risk of tuberculosis (TB), in accordance with animal studies. The present study takes a computational approach toward characterizing the role of TNF in protection against the tubercle bacillus in both active and latent infection. We extend our previous mathematical models to investigate the roles and production of soluble (sTNF) and transmembrane TNF (tmTNF). We analyze effects of anti-TNF therapy in virtual clinical trials (VCTs) by simulating two of the most commonly used therapies, anti-TNF antibody and TNF receptor fusion, predicting mechanisms that explain observed differences in TB reactivation rates. The major findings from this study are that bioavailability of TNF following anti-TNF therapy is the primary factor for causing reactivation of latent infection and that sTNF—even at very low levels—is essential for control of infection. Using a mathematical model, it is possible to distinguish mechanisms of action of the anti-TNF treatments and gain insights into the role of TNF in TB control and pathology. Our study suggests that a TNF-modulating agent could be developed that could balance the requirement for reduction of inflammation with the necessity to maintain resistance to infection and microbial diseases. Alternatively, the dose and timing of anti-TNF therapy could be modified. Anti-TNF therapy will likely lead to numerous incidents of primary TB if used in areas where exposure is likely.
The immune response to Mycobacterium tuberculosis (Mtb) infection is complex. Experimental evidence has revealed that tumor necrosis factor (TNF) plays a major role in host defense against Mtb in both active and latent phases of infection. TNF-neutralizing drugs used to treat inflammatory disorders have been reported to increase the risk of tuberculosis (TB), in accordance with animal studies. The present study takes a computational approach toward characterizing the role of TNF in protection against the tubercle bacillus in both active and latent infection. We extend our previous mathematical models to investigate the roles and production of soluble (sTNF) and transmembrane TNF (tmTNF). We analyze effects of anti-TNF therapy in virtual clinical trials (VCTs) by simulating two of the most commonly used therapies, anti-TNF antibody and TNF receptor fusion, predicting mechanisms that explain observed differences in TB reactivation rates. The major findings from this study are that bioavailability of TNF following anti-TNF therapy is the primary factor for causing reactivation of latent infection and that sTNF-even at very low levels-is essential for control of infection. Using a mathematical model, it is possible to distinguish mechanisms of action of the anti-TNF treatments and gain insights into the role of TNF in TB control and pathology. Our study suggests that a TNFmodulating agent could be developed that could balance the requirement for reduction of inflammation with the necessity to maintain resistance to infection and microbial diseases. Alternatively, the dose and timing of anti-TNF therapy could be modified. Anti-TNF therapy will likely lead to numerous incidents of primary TB if used in areas where exposure is likely.
Mycobacterium tuberculosis (Mtb) is a widespread human pathogen that persists in the lung of latently infected individuals. Control over Mtb infection relies upon migration of leukocytes into the granuloma. We hypothesized that the adhesion molecule ICAM-1 plays a role in the migration, retention and interaction of leukocytes during Mtb infection. While previous studies in ICAM-1−/− mice have indicated that ICAM-1 is required for long-term control over Mtb infection, the mechanism remains unclear. In this study, ICAM-1−/− mice infected with Mtb survived over 10 months post-infection and controlled bacterial burden. Although granuloma formation appeared normal, higher overall cell numbers were observed by H&E staining and flow cytometry. We observed inhibited T cell contraction in the absence of ICAM-1 following primary Mtb infection. T regulatory cells were significantly reduced in ICAM-1−/− mice, which could play a role on T cell contraction. We conclude that ICAM-1 expression helps to control lung pathology by supporting T regulatory cells. Future studies will attempt to elucidate the mechanism by which ICAM-1 affects T regulatory cell recruitment to or retention in the lungs.
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