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Infection and Immunity, January 2005, p. 39-49, Vol. 73, No. 1
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.1.39-49.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Transient Neutralization of Tumor Necrosis Factor Alpha Can Produce a Chronic Fungal Infection in an Immunocompetent Host: Potential Role of Immature Dendritic Cells

Amy C. Herring,1,2 Nicole R. Falkowski,1 Gwo-Hsiao Chen,1 Rod A. McDonald,1 Galen B. Toews,1 and Gary B. Huffnagle1,2*

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine,1 Department of Microbiology and Immunology, University of Michigan Medical Center, Ann Arbor, Michigan2

Received 2 April 2004/ Returned for modification 29 April 2004/ Accepted 1 September 2004

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 naïve 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.

* Corresponding author. Mailing address: Pulmonary and Critical Care Medicine, 6301 MSRB III, The University of Michigan, Ann Arbor, MI 48109-0642. Phone: (734) 936-9369. Fax: (734) 764-4556. E-mail: ghuff{at}umich.edu.

Editor: T. R. Kozel

Infection and Immunity, January 2005, p. 39-49, Vol. 73, No. 1
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.1.39-49.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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