title: Transient neutralization of tumor necrosis factor alpha can produce a chronic fungal infection in an immunocompetent host: potential role of immature dendritic cells.
abstract: The mechanisms underlying induction of immune dysregulation and chronic fungal infection by a transient tumor necrosis factor alpha (TNF-alpha) deficiency remain to be defined. The objective of our studies was to determine the potential contribution of neutropenia and immature dendritic cells to the immune deviation. Administration of an anti-TNF-alpha monoclonal antibody at day 0 neutralized TNF-alpha only during the first week of a pulmonary Cryptococcus neoformans infection. Transient neutralization of TNF-alpha resulted in transient depression of interleukin-12 (IL-12), monocyte chemotactic protein 1 (MCP-1), and gamma interferon (IFN-gamma) production but permanently impaired long-term clearance of the infection from the lungs even after the levels of these cytokines increased and a vigorous inflammatory response developed. Early neutrophil recruitment was defective in the absence of TNF-alpha. However, as demonstrated by neutrophil depletion studies, this did not account for the decrease in IL-12 and IFN-gamma levels and did not play a role in establishing chronic pulmonary cryptococcal infection. Transient TNF-alpha neutralization also produced a deficiency in CD11c(+) MHC II(+) cells and IL-12 in the lymph nodes, potentially implicating a defect in mature dendritic cell trafficking. Transfer of cryptococcal antigen-pulsed immature dendritic cells into naive mice prior to intratracheal challenge resulted in the development of a nonprotective immune response to C. neoformans that was similar to that observed in anti-TNF-alpha-treated mice (increased IL-4, IL-5, and IL-10 levels, pulmonary eosinophilia, and decreased clearance). Thus, stimulation of an antifungal response by immature dendritic cells can result in an immune deviation similar to that produced by transient TNF-alpha deficiency, identifying a new mechanism by which a chronic fungal infection can occur in an immunocompetent host.
authors.affiliation: Pulmonary and Critical Care Medicine, 6301 MSRB III, The University of Michigan, Ann Arbor, MI 48109-0642, USA.
authors.forename: Amy C
authors.initials: AC
authors.lastname: Herring
authors.forename: Nicole R
authors.initials: NR
authors.lastname: Falkowski
authors.forename: Gwo-Hsiao
authors.initials: GH
authors.lastname: Chen
authors.forename: Rod A
authors.initials: RA
authors.lastname: McDonald
authors.forename: Galen B
authors.initials: GB
authors.lastname: Toews
authors.forename: Gary B
authors.initials: GB
authors.lastname: Huffnagle
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000096:biosynthesis; D002908:Chronic Disease; D003453:Cryptococcosis / Q000276:immunology*; D003713:Dendritic Cells / Q000502:physiology*; D007121:Immunocompetence; D018664:Interleukin-12 / Q000096:biosynthesis; D007962:Leukocytes / Q000502:physiology; D008172:Lung Diseases, Fungal / Q000276:immunology*; D051379:Mice; D008808:Mice, Inbred CBA; D009181:Mycoses / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12