Abstract
We assessed the effect of modified antigen presenting cells (APCs) expressing high levels of Fas ligand (APC-FasL) on post-viral chronic inflammatory disease. FasL-deficient B6-gld/gld mice infected with murine cytomegalovirus (MCMV) cleared the virus from their lungs, kidneys, and livers within 2 weeks of infection. However, inflammation persisted in these organs for more than 8 weeks, with a chronically increased T-cell response to MCMV-infected APCs and production of autoantibodies. Administration of APC-AdFasL at 4 weeks suppressed this inflammation and diminished the T-cell response and autoantibody production. APC-AdFasL that had been transfected with ultraviolet-irradiated MCMV were more effective than uninfected APC-AdFasL in ameliorating the chronic inflammation. APC-AdFasL migrated preferentially to the spleen, where they triggered apoptosis of lymphocytes in the marginal zone of the spleen. These results confirm that Fas-mediated apoptosis is not required for clearance of virus, but is required for down-modulation of the virally induced chronic inflammatory response. This organwide effect of APC-AdFasL appears to be mediated by elimination of activated T lymphocytes in the spleen before their emigration to the target organs.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenoviridae / genetics
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Animals
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Antigen-Presenting Cells / immunology*
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Antigen-Presenting Cells / transplantation
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Apoptosis*
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Autoantibodies / biosynthesis
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Cytomegalovirus Infections / immunology*
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Cytomegalovirus Infections / pathology
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Cytomegalovirus Infections / therapy
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Fas Ligand Protein
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Female
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Genetic Vectors / genetics
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Hepatitis, Viral, Animal / etiology
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Hepatitis, Viral, Animal / immunology
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Hepatitis, Viral, Animal / pathology
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Inflammation
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Kidney / pathology
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Liver / pathology
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Lung / pathology
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Lung Diseases, Interstitial / etiology
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Lung Diseases, Interstitial / immunology
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Lung Diseases, Interstitial / pathology
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Macrophages / immunology
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Membrane Glycoproteins / deficiency
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / physiology*
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Mice
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Mice, Inbred BALB C
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Mice, Inbred MRL lpr
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Mice, Mutant Strains
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Nephritis / etiology
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Nephritis / immunology
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Nephritis / pathology
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Specific Pathogen-Free Organisms
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Spleen / immunology
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Spleen / pathology
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T-Lymphocyte Subsets / immunology
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Transfection
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fas Receptor / physiology
Substances
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Autoantibodies
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Fas Ligand Protein
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Fasl protein, mouse
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Membrane Glycoproteins
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fas Receptor