title: CCR5 deficiency mitigates the deleterious effects of tumor necrosis factor α antagonism in murine histoplasmosis.
abstract: In murine histoplasmosis, tumor necrosis factor α (TNF-α) antagonism increases the number of regulatory T cells (Tregs) in lungs, and these cells profoundly hinder protective immunity. Because CCR5 mediates Treg homing and proliferation, we determined the outcome of antagonizing TNF-α in CCR5(-/)(-) mice infected with Histoplasma capsulatum. The absence of CCR5 attenuated the severity of infection associated with TNF-α neutralization. Infected controls given anti-TNF-α had a 10-fold increase in the number of Tregs in lungs compared with a <2-fold increase in CCR5(-/)(-) lungs. This difference was partially attributable to impaired homing in the absence of CCR5. Neutralization of TNF-α-enhanced CCR5 ligands in wild-type lungs thus promotes a gradient between lungs and the thymus. This study elucidates the interplay between TNF-α and CCR5 in histoplasmosis. The data suggest that targeting CCR5 may improve host immunity in individuals receiving TNF-α antagonists during infection.
authors.affiliation: Department of Molecular Genetics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: Danielle N
authors.initials: DN
authors.lastname: Kroetz
authors.forename: George S
authors.initials: GS
authors.lastname: Deepe
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D049109:Cell Proliferation; D006658:Histoplasma / Q000472:pathogenicity; D006660:Histoplasmosis / Q000276:immunology* / Q000473:pathology; D008168:Lung / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019713:Receptors, CCR5 / Q000172:deficiency*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D019713:Receptors, CCR5; D014409:Tumor Necrosis Factor-alpha