title: Neutralization of tumor necrosis factor (TNF) by antibody but not TNF receptor fusion molecule exacerbates chronic murine tuberculosis.
abstract: Tumor necrosis factor (TNF) plays an essential role in the immunologic maintenance of Mycobacterium tuberculosis infection. Although an increased rate of tuberculosis has been reported in humans treated with anti-TNF biological agents, disparate rates of disease have been observed between those treated with infliximab, an anti-TNF antibody, and etanercept, a TNF-neutralizing TNF receptor (TNFR) fusion molecule. We compared the effects of anti-TNF antibody and soluble TNFR fusion molecule in the murine model of tuberculosis. Systemic TNF neutralization was equivalent between these molecules, and both resulted in rapid morbidity at the initiation of infection. During chronic infection, administration of the receptor fusion molecule allowed the control of infection, whereas antibody treatment caused mice to die within a month. We provide evidence of decreased penetration into the granulomas by the receptor fusion molecule, compared with antibody. These findings begin to clarify the mechanistic difference between anti-TNF agents and their role in the exacerbation of tuberculosis.
authors.affiliation: Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Hillarie L
authors.initials: HL
authors.lastname: Plessner
authors.forename: P Ling
authors.initials: PL
authors.lastname: Lin
authors.forename: Tadahiko
authors.initials: T
authors.lastname: Kohno
authors.forename: James S
authors.initials: JS
authors.lastname: Louie
authors.forename: Denise
authors.initials: D
authors.lastname: Kirschner
authors.forename: John
authors.initials: J
authors.lastname: Chan
authors.forename: Joanne L
authors.initials: JL
authors.lastname: Flynn
mesh_terms: D000208:Acute Disease; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D002908:Chronic Disease; D003176:Complement C3 / Q000172:deficiency / Q000378:metabolism; D000068800:Etanercept; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology* / Q000627:therapeutic use; D008168:Lung / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy / Q000276:immunology / Q000382:microbiology / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D003176:Complement C3; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept