title: Tumor necrosis factor-alpha antagonism by the murine tumor necrosis factor-alpha receptor 2-Fc fusion protein exacerbates histoplasmosis in mice.
abstract: Treatment of some inflammatory conditions with tumor necrosis factor-alpha (TNF-alpha) antagonists is efficacious, but such treatments are associated with infections with intracellular pathogens, including Histoplasma capsulatum. We explored protective immunity to H. capsulatum in mice given a fusion protein consisting of TNF-alpha receptor 2 (TNFR2) bound to the Fc portion of mouse IgG1. Intraperitoneal administration of this inhibitor exacerbated primary or secondary pulmonary infection at dosages ranging from 1 to 5 mg/kg. All mice with primary infection given the inhibitor succumbed to infection within 10-21 days of treatment. In secondary histoplasmosis, mice receiving 1, but not 5, mg/kg survived treatment. Fungal burden was increased even if treatment with the inhibitor was initiated after the onset of infection. The inflammatory response of the lungs of mice given the inhibitor did not differ from that of mice given control vehicle. Susceptibility was not associated with major alterations in cytokines known to protect or exacerbate infection. However, expression of nitric oxide synthase 2 (NOS2) was depressed early in primary infection. These results demonstrate that antagonism of endogenous TNF-alpha by this fusion protein modulates susceptibility. Impaired immunity is not a result of altered cytokine responses or changes in the inflammation and may not be demonstrable in other murine strains.
authors.affiliation: Division of Infectious Diseases, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0560, USA. george.deepe@uc.edu
authors.forename: George S
authors.initials: GS
authors.lastname: Deepe
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D016207:Cytokines / Q000235:genetics; D018450:Disease Progression; D005786:Gene Expression Regulation; D006658:Histoplasma / Q000502:physiology; D006660:Histoplasmosis / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D007141:Immunoglobulin Fc Fragments / Q000009:adverse effects / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000009:adverse effects / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D016207:Cytokines; D007141:Immunoglobulin Fc Fragments; D047889:Receptors, Tumor Necrosis Factor, Type II; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D052247:Nitric Oxide Synthase Type II