Differential Risk of Tuberculosis Reactivation among Anti-TNF Therapies Is Due to Drug Binding Kinetics and Permeability This information is current as of September 26, 2021. Mohammad Fallahi-Sichani, JoAnne L. Flynn, Jennifer J. Linderman and Denise E. Kirschner J Immunol 2012; 188:3169-3178; Prepublished online 29 February 2012; doi: 10.4049/jimmunol.1103298 Downloaded from http://www.jimmunol.org/content/188/7/3169 Supplementary http://www.jimmunol.org/content/suppl/2012/02/29/jimmunol.110329 http://www.jimmunol.org/ Material 8.DC1 References This article cites 59 articles, 21 of which you can access for free at: http://www.jimmunol.org/content/188/7/3169.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 26, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2012 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Differential Risk of Tuberculosis Reactivation among Anti-TNF Therapies Is Due to Drug Binding Kinetics and Permeability Mohammad Fallahi-Sichani,*,1 JoAnne L. Flynn,† Jennifer J. Linderman,* and Denise E. Kirschner‡ Increased rates of tuberculosis (TB) reactivation have been reported in humans treated with TNF-a (TNF)-neutralizing drugs, and higher rates are observed with anti-TNF Abs (e.g., infliximab) as compared with TNF receptor fusion protein (etanercept). Mechanisms driving differential reactivation rates and differences in drug action are not known. We use a computational model of a TB granuloma formation that includes TNF/TNF receptor dynamics to elucidate these mechanisms. Our analyses yield three important insights. First, drug binding to membrane-bound TNF critically impairs granuloma function. Second, a higher risk Downloaded from of reactivation induced from Ab-type treatments is primarily due to differences in TNF/drug binding kinetics and perme- ability. Apoptotic and cytolytic activities of Abs and pharmacokinetic fluctuations in blood concentration of drug are not essen- tial to inducing TB reactivation. Third, we predict specific host factors that, if augmented, would improve granuloma function during anti-TNF therapy. Our findings have implications for the development of safer anti-TNF drugs to treat inflammatory diseases. The Journal of Immunology, 2012, 188: 3169–3178. http://www.jimmunol.org/ ycobacterium tuberculosis is the causative agent of state of infection in the host. TNF plays an important role in tuberculosis (TB) in humans. Although TB is a global regulating granuloma function, defined here as the ability of M health problem with 2 billion people infected, most are a granuloma to restrict bacterial growth (4, 5, 7–10). TNF, a in a latent state, controlling infection. The incidence of active TB pleiotropic cytokine produced by infected and activated macro- is increased in patients with inflammatory conditions such as phages and proinflammatory T cells (3, 11), has been shown to rheumatoid arthritis (RA) and psoriasis receiving treatment with enhance macrophage activation (12), chemokine production by TNF-a (TNF) inhibitors (1, 2). Mice, monkeys, and zebrafish also macrophages (13), and recruitment of immune cells during M. exhibit impaired immunity during M. tuberculosis infection in the tuberculosis infection (14). TNF can also mediate cell death via absence of TNF (3–5). These observations support a central role inducing the caspase-mediated apoptotic pathway (15). Neutrali- by guest on September 26, 2021 for TNF in maintaining immunity to M. tuberculosis. However, zation of TNF can lead to uncontrolled growth of bacteria and these findings also represent a major challenge to anti-TNF ther- reactivation of latent TB (4). apy use for inflammatory diseases. Excellent therapies that are currently licensed as TNF inhibitors The key pathological feature that forms during the immune are oftwo types: anti-TNF mAbs (includinginfliximab,adalimumab, response to M. tuberculosis is a spherical collection of immune and certolizumab) or soluble TNF receptor fusion proteins (eta- cells and bacteria termed a granuloma (6); the collection of nercept) (16). These drugs have been reported to be equally and granulomas successfully limiting bacteria growth defines a latent highly effective in treatment of some (but not all) inflammatory diseases such as RA and psoriatic arthritis (17, 18). However, recent studies have shown the risk of TB reactivation posed by Ab-type *Department of Chemical Engineering, University of Michigan, Ann Arbor, MI drugs to be several-fold greater than for soluble TNF receptor-type 48109; †Department of Microbiology and Molecular Genetics, University of Pitts- burgh School of Medicine, Pittsburgh, PA 15261; and ‡Department of Microbiology drugs (19–21). Several hypotheses based on differences in drug and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109 properties (reviewed in Refs. 16, 22–26) have been advanced to 1Current address: Department of Systems Biology, Harvard Medical School, Boston, explain the observed differential risk of TB reactivation among anti- MA. TNF therapies. However, no mechanisms have been definitively Received for publication November 18, 2011. Accepted for publication January 22, identified. For our study, we categorize these drug properties into 2012. four groups: 1) TNF binding properties (including affinity, binding/ This work was supported by National Institutes of Health Grants R33HL092844, unbinding kinetics, stoichiometry, and ability to bind membrane- R33HL092853, R01 EB012579-04A1, R01 HL106804-01, R01 HL71241, 1R01 HL106804, and R33 HL092883, as well as by a University of Michigan Rackham bound TNF [mTNF]), 2) permeability (from blood vessels into lung Predoctoral Fellowship (to M.F.-S.). tissue and penetration into the granuloma), 3) apoptotic and cyto- Address correspondence and reprint requests to Dr. Jennifer J. Linderman, Depart- lytic activity, and 4) pharmacokinetic (PK) characteristics. ment of Chemical Engineering, University of Michigan, 2300 Hayward Street, Ann Information on these four drug properties is available for clin- Arbor, MI 48109. E-mail address: [email protected] ically used TNF inhibitors (12, 16, 27). TNF binding kinetics for The online version of this article contains supplemental material. etanercept, infliximab and adalimumab have been measured (28, Abbreviations used in this article: ABM, agent-based model; CDC, complement- dependent cytotoxicity; LHS, Latin hypercube sampling; mTNF, membrane-bound 29), and each binds both mTNF and soluble TNF (sTNF). Up to TNF-a; ODE, ordinary differential equation; PK, pharmacokinetic; PRCC, partial three molecules of Ab-type drugs can bind each TNF molecule, but rank correlation coefficient; RA, rheumatoid arthritis; sTNF, soluble TNF-a; TACE, etanercept binds TNF with a binding ratio of 1:1 (30). TNF binding TNF-a converting enzyme; TB, tuberculosis; TNF, TNF-a. properties can influence TNF concentration in granulomatous tis- Copyright Ó 2012 by The American Association of Immunologists, Inc. 0022-1767/12/$16.00 sue and affect immunity to M. tuberculosis (26, 31). A recent study www.jimmunol.org/cgi/doi/10.4049/jimmunol.1103298 3170 MODELING OF TUBERCULOSIS REACTIVATION has provided evidence of decreased permeability of soluble TNF renchyma via vascular sources and diffuses among microcompartments receptors in mouse granulomas compared with anti-TNF Ab (25). (Fig. 1C). The flux of a drug from a blood vessel into the tissue is related to Infliximab and adalimumab, but not etanercept and certolizumab, the vascular permeability coefficient of the drug (kc) and the drug gradient across the vessel wall by: induce apoptosis in TNF-expressing cells (27, 32–34). This might be related to the ability of infliximab and adalimumab, as well as ∂½Drug 2D j ¼ k ðC 2 ½Drug Þ; ð1Þ the inability of etanercept and certolizumab, to cross-link mTNF drug ∂r r¼0 c p r¼0 (27). Finally, PK data, including blood concentration/time profiles, where Cp is the concentration of the drug in blood, [Drug] is the concentration are available for etanercept, infliximab, and adalimumab as ad- of the drug in tissue that is a function of time and distance from the vessel (r), ministered in RA and psoriasis patients (35). It is not clear how [Drug]r=0 is the concentration of the drug at the outside wall of the vessel, these four drug properties, alone or in combination, contribute to and Ddrug is the drug diffusion coefficient in tissue. Using this equation and rearranging it for discrete-space flux on the two-dimensional grid gives: observed differences in reactivation of TB induced by anti-TNF treatments, and laboratory experiments needed to explore this in 1 D fC 2 þ C þ C 2 þ C gþC k dx 4 drug i 1;j iþ1;j i;j 1 i;jþ1 p c vivo are currently not feasible. Csource ¼ Ci; j ¼ ; We recently used a systems biology approach to track formation Ddrug þ kcdx and maintenance of a TB granuloma in lung tissue in space and ð2Þ time (7, 8, 36). Our multiscale computational model captures the where Csource = Ci,j represents the drug concentration at the outside wall of dynamics of TNF/TNFR interactions that occur on second to the vascular source located at the microcompartment (i,j) and dx (=20 mm) minute time scales within the long-term cellular immune response is the lattice spacing through which diffusion occurs. Equation 2 implies →‘ to M. tuberculosis (8). Our model also provides detailed infor- that at very large vascular permeabilities (kc ), Ci,j tends to blood Downloaded from concentration of the drug (C ).