Altered tissue distribution of viral replication and T cell spreading is pivotal in the protection against fatal lymphocytic choriomeningitis in mice after neutralization of IFN-alpha/beta.
IFN-alpha/beta have been shown to play a central role in the development of lymphocytic choriomeningitis and increasing attention has been focused on this group of cytokines as early regulatory factors directing T lymphocyte responses. In the present study, injection of antiserum to IFN-alpha/beta prevented the development of lymphocytic choriomeningitis, was associated with the absence of detectable expression of early 2'-5' oligo-adenylate synthetase mRNA and coincided with viremia of lymphocytic choriomeningitis virus (LCMV) followed by establishment of a persistent infection. The LCMV-specific cytotoxic T lymphocyte response was unchanged in cervical lymph nodes but decreased in the spleen of anti-IFN-alpha/beta-treated animals. The expression of cytokine mRNA (particularly IFN-gamma) in organs of LCMV-infected mice treated with anti-IFN-alpha/beta coincided with infiltration of lymphocytes and tissue destruction. Furthermore, a reduced number of infiltrating leukocytes in the brain and cervical lymph nodes and a low expression of cytokine mRNA in the brain was observed in anti-IFN-alpha/beta-treated animals. In total, the findings support the view that neutralization of IFN-alpha/beta leads to extensive LCMV replication in the viscera. The therapeutic effects of anti-IFN-alpha/beta antiserum seem to be independent of the functional capacity of T cells but probably result in a dispersion of activated T cells throughout the body of LCMV-infected mice. Absence of IFN-alpha/beta expression in the central nervous system is proposed as the mechanism behind the IFN-alpha/beta-dependent targeting of T cells to the brain.
Sandberg
K
K
Department of Neuropharmacology, Scripps Research Institute, La Jolla, CA 92037.
Kemper
P
P
Stalder
A
A
Zhang
J
J
Hobbs
M V
MV
Whitton
J L
JL
Campbell
I L
IL
D015088:2',5'-Oligoadenylate Synthetase / Q000235:genetics; D000818:Animals; D000937:Antigen-Antibody Reactions; D016516:CD4-CD8 Ratio; D002448:Cell Adhesion; D016207:Cytokines / Q000235:genetics; D003602:Cytotoxicity, Immunologic; D015870:Gene Expression; D007370:Interferon Type I / Q000037:antagonists & inhibitors / Q000276:immunology*; D008213:Lymphocyte Activation; D008216:Lymphocytic Choriomeningitis / Q000276:immunology* / Q000382:microbiology / Q000517:prevention & control; D008217:Lymphocytic choriomeningitis virus / Q000254:growth & development; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000235:genetics; D013601:T-Lymphocytes / Q000166:cytology / Q000382:microbiology*; D014018:Tissue Distribution; D014779:Virus Replication
D016207:Cytokines; D007370:Interferon Type I; D012333:RNA, Messenger; D015088:2',5'-Oligoadenylate Synthetase