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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 of reactivation induced from Ab-type treatments is primarily due to differences in TNF\/drug binding kinetics and permeability. Apoptotic and cytolytic activities of Abs and pharmacokinetic fluctuations in blood concentration of drug are not essential 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.<\/jats:p>","DOI":"10.4049\/jimmunol.1103298","type":"journal-article","created":{"date-parts":[[2012,3,1]],"date-time":"2012-03-01T01:30:57Z","timestamp":1330565457000},"page":"3169-3178","source":"Crossref","is-referenced-by-count":93,"title":["Differential Risk of Tuberculosis Reactivation among Anti-TNF Therapies Is Due to Drug Binding Kinetics and Permeability"],"prefix":"10.1093","volume":"188","author":[{"given":"Mohammad","family":"Fallahi-Sichani","sequence":"first","affiliation":[{"name":"Department of Chemical Engineering, University of Michigan , Ann Arbor, MI 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"JoAnne L","family":"Flynn","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine , Pittsburgh, PA 15261"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer J","family":"Linderman","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering, University of Michigan , Ann Arbor, MI 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise E","family":"Kirschner","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Michigan Medical School , Ann Arbor, MI 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2012,4,1]]},"reference":[{"key":"2025032409594415600_r1","doi-asserted-by":"crossref","first-page":"S194","DOI":"10.1086\/429996","article-title":"Reactivation of latent granulomatous infections by infliximab","volume":"41","author":"Wallis","year":"2005","journal-title":"Clin. 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