title: Differential risk of tuberculosis reactivation among anti-TNF therapies is due to drug binding kinetics and permeability.
abstract: Increased rates of tuberculosis (TB) reactivation have been reported in humans treated with TNF-α (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 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.
authors.affiliation: Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Fallahi-Sichani
authors.forename: JoAnne L
authors.initials: JL
authors.lastname: Flynn
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Linderman
authors.forename: Denise E
authors.initials: DE
authors.lastname: Kirschner
mesh_terms: D000068879:Adalimumab; D000911:Antibodies, Monoclonal / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D018501:Antirheumatic Agents / Q000009:adverse effects* / Q000097:blood / Q000145:classification / Q000493:pharmacokinetics; D017209:Apoptosis / Q000187:drug effects; D000068582:Certolizumab Pegol; D003198:Computer Simulation; D003602:Cytotoxicity, Immunologic; D000068800:Etanercept; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000009:adverse effects / Q000097:blood; D007074:Immunoglobulin G / Q000009:adverse effects / Q000097:blood; D000069285:Infliximab; D055985:Latent Tuberculosis / Q000276:immunology / Q000503:physiopathology*; D008954:Models, Biological; D009169:Mycobacterium tuberculosis / Q000254:growth & development* / Q000276:immunology; D010539:Permeability; D011092:Polyethylene Glycols / Q000009:adverse effects / Q000493:pharmacokinetics; D011485:Protein Binding; D018124:Receptors, Tumor Necrosis Factor / Q000097:blood / Q000187:drug effects* / Q000502:physiology; D012306:Risk; D014375:Tuberculoma / Q000276:immunology / Q000382:microbiology / Q000503:physiopathology*; D014397:Tuberculosis, Pulmonary / Q000276:immunology / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D011092:Polyethylene Glycols; D000069285:Infliximab; D000068879:Adalimumab; D000068800:Etanercept; D000068582:Certolizumab Pegol