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A Mouse Model for Pathogen-induced Chronic Inflammation at Local and Systemic Sites
Published on: August 8, 2014
Antigen presenting cells expressing Fas ligand down-modulate chronic inflammatory disease in Fas ligand-deficient
1Department of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama-Birmingham, Birmingham, Alabama 35294, USA.
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.
Insights
Modified antigen-presenting cells (APCs) expressing Fas ligand (APC-FasL) effectively suppressed chronic inflammation post-viral infection. This Fas-mediated apoptosis targets T lymphocytes, preventing persistent disease.
Area of Science:
- Immunology
- Virology
- Cell Biology
Background:
- Post-viral chronic inflammation can persist despite viral clearance.
- Fas ligand (FasL) plays a role in immune regulation.
- Murine cytomegalovirus (MCMV) infection in FasL-deficient mice leads to chronic inflammation.
Purpose of the Study:
- To investigate the therapeutic potential of modified antigen-presenting cells (APCs) expressing Fas ligand (APC-FasL) in treating post-viral chronic inflammation.
- To elucidate the mechanism by which APC-FasL modulates the immune response.
Main Methods:
- Utilized FasL-deficient B6-gld/gld mice infected with MCMV.
- Administered modified APCs expressing Fas ligand (APC-AdFasL) at 4 weeks post-infection.
- Compared efficacy of APC-AdFasL transfected with ultraviolet-irradiated MCMV versus uninfected APC-AdFasL.
- Tracked APC-AdFasL migration and lymphocyte apoptosis in the spleen.
Main Results:
- Mice cleared MCMV but exhibited persistent inflammation and elevated T-cell responses.
- APC-AdFasL treatment significantly suppressed chronic inflammation, T-cell responses, and autoantibody production.
- APCs transfected with irradiated MCMV showed enhanced therapeutic effects.
- APC-AdFasL preferentially migrated to the spleen, inducing apoptosis of marginal zone lymphocytes.
Conclusions:
- Fas-mediated apoptosis is crucial for down-modulating virally induced chronic inflammation, not for initial viral clearance.
- APC-FasL therapy ameliorates chronic inflammation by eliminating activated T lymphocytes in the spleen.
- Targeting splenic lymphocytes via APC-FasL offers a potential strategy for treating chronic inflammatory diseases.
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