Differences in reactivation of tuberculosis induced from anti-TNF treatments are based on bioavailability in granulomatous tissue

Abstract

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.

A mathematical model of pulmonary gas exchange under inflammatory stress

“…With the exception of mycobacterial granuloma formation modeling (Marino et al, 2004; Marino et al, 2007), attempts at mathematical simulation of lung injury have been sparse, although pulmonary immunity and injury are of immense clinical interest and relevance. Immune-mediated lung injury has typically only been approached with experimental models.…”

Rheumatoid arthritis and herpes zoster: risk and prevention in those treated with anti-tumour necrosis factor therapy

“…The inconsistent results for anti-TNF therapy, however, are confusing and in stark contrast to the increased risks observed for anti-TNF therapy with tuberculosis and other granulomatous pathogens, where a mechanism of action has been demonstrated in vitro and in animal models 14–16. One could hypothesise that TNF antagonist-driven downregulation of interferonγ could promote varicella reactivation, however a firm hypothesis and experimental evidence are currently lacking.…”

TNF and IL-10 are major factors in modulation of the phagocytic cell environment in lung and lymph node in tuberculosis: A next-generation two-compartmental model

“…We previously developed a series of mathematical models that qualitatively and quantitatively characterize the cellular and cytokine network during infection in lung (Marino et al, 2007; Sud et al, 2006; Wigginton and Kirschner, 2001), and in lung and LN (Marino and Kirschner, 2004; Marino et al, 2004). In this work our goal is to develop the next-generation two-compartmental model to investigate more mechanistic details involved in the immune response during Mycobacterium tuberculosis infection.…”