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Journal of Virology, July 1999, p. 5918-5925, Vol. 73, No. 7
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Thymic Tolerance to Only One Viral Protein Reduces Lymphocytic Choriomeningitis Virus-Induced Immunopathology and Increases Survival in Perforin-Deficient Micedagger

Matthias von Herrath,1,* Bryan Coon,1 Dirk Homann,1 Tom Wolfe,1 and Luca G. Guidotti2

Department of Neuropharmacology, Division of Virology,1 and Department of Molecular and Experimental Medicine,2 The Scripps Research Institute, La Jolla, California 92037

Received 27 January 1999/Accepted 26 March 1999

The outcome of viral infections is dependent on the amount of tissue destruction caused either by direct lysis of infected cells and/or by immunopathology resulting from the immune response to the virus. We investigated whether induction of tolerance to only one viral protein could reduce immunopathology caused by nonlytic lymphocytic choriomeningitis virus (LCMV) in perforin-deficient hosts. Earlier studies had shown that LCMV infection results in aplastic anemia and death in most of these mice and that this is associated with bone marrow infiltration by antiviral cytotoxic T lymphocytes (CTL) that secrete inflammatory cytokines. We report here that perforin-deficient mice exhibit severe immunopathology in multiple organs that is characterized by infiltration of anti-LCMV CTL that secrete large amounts of gamma interferon (IFN-gamma ) and tumor necrosis factor alpha (TNF-alpha ). Importantly, this immunopathology is significantly reduced and long-term survival of LCMV infection is increased in perforin-deficient mice expressing LCMV nucleoprotein (NP) in the thymus (and therefore deleting most of their LCMV-NP CTL) compared to the situation in thymus nonexpressors. This is due to the selective reduction of NP-specific CTL responses and their inflammatory-cytokine (IFN-gamma and TNF-alpha ) secretion and to a lack of pathogenetically relevant compensatory responses to other viral proteins. Thus, "selective reduction" of the antiviral immune response to only one viral protein can significantly reduce inflammatory immunopathology and might be a therapeutic possibility for certain nonlytic infections.

* Corresponding author. Mailing address: Department of Neuropharmacology, Division of Virology, IMM6, The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, CA 92037. Phone: (619) 784-9602. Fax: (619) 784-9981. E-mail: matthias{at}scripps.edu.

dagger Publication 11705-NP from the Division of Virology, Department of Neuropharmacology, The Scripps Research Institute.

Journal of Virology, July 1999, p. 5918-5925, Vol. 73, No. 7
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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