A model on the influence of age on immunity to infection with Mycobacterium tuberculosis

Friedman, Avner; Turner, Joanne; Szomolay, Barbara

doi:10.1016/j.exger.2007.12.004

Cited by 35 publications

(41 citation statements)

References 30 publications

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“…By including essential details of the drug-drug and host-drug-bacteria interactions, such a systems-level mathematical model for combination drug therapy against TB in mice can, in principle, simulate a variety of experimental studies and generate hypotheses regarding the efficacy of drug regimens that are not initially tested. While systems biology approaches have been used previously to describe the immune response to M. tuberculosis infection (14), both in humans (15) and in mice (16), efforts to include pharmacokinetics have been limited to human disease (17,18). Additionally, these pharmacokinetic submodels incorporated minimal experimental data compared to data which is otherwise obtainable in animal models.…”

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confidence: 99%

A Physiologically Based Pharmacokinetic Model of Rifampin in Mice

Lyons

Reisfeld

Yang

et al. 2013

Antimicrob Agents Chemother

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One problem associated with regimen-based development of antituberculosis (anti-TB) drugs is the difficulty of a systematic and thorough in vivo evaluation of the large number of possible regimens that arise from consideration of multiple drugs tested together. A mathematical model capable of simulating the pharmacokinetics and pharmacodynamics of experimental combination chemotherapy of TB offers a way to mitigate this problem by extending the use of available data to investigate regimens that are not initially tested. In order to increase the available mathematical tools needed to support such a model for preclinical anti-TB drug development, we constructed a preliminary whole-body physiologically based pharmacokinetic (PBPK) model of rifampin in mice, using data from the literature. Interindividual variability was approximated using Monte Carlo (MC) simulation with assigned probability distributions for the model parameters. An MC sensitivity analysis was also performed to determine correlations between model parameters and plasma concentration to inform future model development. Model predictions for rifampin concentrations in plasma, liver, kidneys, and lungs, following oral administration, were generally in agreement with published experimental data from multiple studies. Sensitive model parameters included those descriptive of oral absorption, total clearance, and partitioning of rifampin between blood and muscle. This PBPK model can serve as a starting point for the integration of rifampin pharmacokinetics in mice into a larger mathematical framework, including the immune response to Mycobacterium tuberculosis infection, and pharmacokinetic models for other anti-TB drugs.T uberculosis (TB), caused by Mycobacterium tuberculosis, is an infectious disease which continues to be a major cause of death in large parts of the world (1). While the current first-line therapy for drug-susceptible TB (composed of rifampin, isoniazid, pyrazinamide, and ethambutol) has been in clinical use for nearly 30 years, the emergence and spread of drug-resistant M. tuberculosis strains have motivated the search for new, more-effective combination regimens (2). Our interest here is the development of mathematical tools to supplement the animal studies necessary for the identification and testing of such new anti-TB drug regimens.The mouse is the primary animal species used for preclinical anti-TB drug development (3). Despite the differences between mice and humans, the activities of many anti-TB drugs against disease caused by M. tuberculosis are similar in both species (4, 5). Mice also provide for a range of TB susceptibility and pathology through a variety of outbred and inbred strains; a notable example is C3HeB/FeJ mice (6), which form necrotic pulmonary lesions similar to those observed in TB patients (7). The recent Critical Path to TB Drug Regimens (CPTR) Initiative (8) includes an added emphasis on the mouse for identification of new optimized three-drug regimens as a key step in advancing novel drug combinations into ...

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confidence: 99%

A Physiologically Based Pharmacokinetic Model of Rifampin in Mice

Lyons

Reisfeld

Yang

et al. 2013

Antimicrob Agents Chemother

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“…The present article builds on some of this work and on other models of tuberculosis (19)(20)(21). However, these former models of tuberculosis infection do not specifically consider AAM and instead focus on the paradigm involving only macrophage populations (resting, activated, and infected) that are activated/primed by IFN-␥/TNF-␣ (i.e., CAM) Although it is clear that during the course of an MTb infection CAM are involved, the present work focuses on the fact that AAM are the first to encounter and respond to MTb.…”

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Modeling the immune rheostat of macrophages in the lung in response to infection

Day¹,

Friedman²,

Schlesinger

2009

Proc. Natl. Acad. Sci. U.S.A.

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126

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In the lung, alternatively activated macrophages (AAM) form the first line of defense against microbial infection. Due to the highly regulated nature of AAM, the lung can be considered as an immunosuppressive organ for respiratory pathogens. However, as infection progresses in the lung, another population of macrophages, known as classically activated macrophages (CAM) enters; these cells are typically activated by IFN-␥. CAM are far more effective than AAM in clearing the microbial load, producing proinflammatory cytokines and antimicrobial defense mechanisms necessary to mount an adequate immune response. Here, we are concerned with determining the first time when the population of CAM becomes more dominant than the population of AAM. This proposed ''switching time'' is explored in the context of Mycobacterium tuberculosis (MTb) infection. We have developed a mathematical model that describes the interactions among cells, bacteria, and cytokines involved in the activation of both AAM and CAM. The model, based on a system of differential equations, represents a useful tool to analyze strategies for reducing the switching time, and to generate hypotheses for experimental testing.alternatively activated macrophages ͉ lung innate immunity ͉ mycobacteria tuberculosis

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“…Currently, in Japan, more than 50% of the new cases of TB occur in patients Ն60 years old (29). The increasing susceptibility of the elderly to M. tuberculosis is generally thought to be associated with immune senescence, the most significant change being the loss or delayed production of antigen-specific CD4 ϩ T cells (14). In mice, an inadequate antigen-specific CD4 ϩ T-cell response is thought to contribute to increased susceptibility to M. tuberculosis infection (27).…”

Section: Discussionmentioning

confidence: 99%

Influence of Advanced Age onMycobacterium bovisBCG Vaccination in Guinea Pigs Aerogenically Infected withMycobacterium tuberculosis

Komine‐Aizawa

Yamazaki

et al. 2010

Clin Vaccine Immunol

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Mycobacterium bovis bacillus Calmette-Guérin (BCG) is the only tuberculosis (TB) vaccine currently available, but its efficacy against adult pulmonary TB remains controversial. BCG induces specific immune responses to mycobacterial antigens and may elicit protective immunity against TB. TB remains a major public health problem, especially among the elderly, yet the efficacy of BCG in the elderly is unknown. We investigated the ability of BCG vaccination to prevent TB in young (6-week-old), middle-aged (18-month-old), and old (60-month-old) guinea pigs. BCG-Tokyo vaccination reduced the growth of Mycobacterium tuberculosis H37Rv in all three groups. By use of an enzyme-linked immunospot (ELISPOT) assay, antigen-specific gamma interferon (IFN-␥)-producing cells were detected in the 60-month-old guinea pigs after a booster vaccination with BCG-Tokyo. Our findings suggest that BCG-Tokyo has a protective effect against tuberculosis infection regardless of age.

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A model on the influence of age on immunity to infection with Mycobacterium tuberculosis

Cited by 35 publications

References 30 publications

A Physiologically Based Pharmacokinetic Model of Rifampin in Mice

A Physiologically Based Pharmacokinetic Model of Rifampin in Mice

Modeling the immune rheostat of macrophages in the lung in response to infection

Influence of Advanced Age onMycobacterium bovisBCG Vaccination in Guinea Pigs Aerogenically Infected withMycobacterium tuberculosis

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