Effects of IL-12 on the response and susceptibility to experimental viral infections.
Effects of administered IL-12 on immune responses to viral infection were evaluated. IL-12-mediated effects during lymphocytic choriomeningitis virus (LCMV) infection in C57BL/6 mice were contrasted to those in either uninfected mice, or mice infected with a virus inducing a more modest T cell response, murine cytomegalovirus. Mice received 0, 1, 10, 100, or 1000 ng/d of IL-12 on the day prior to infection and daily on day 0 to 6 post-infection. Responses were examined on day 7. Low doses of IL-12 enhanced immunity to LCMV infection as demonstrated by increased splenic CD8+ T cell numbers and decreased LCMV replication. Low doses of IL-12 also significantly enhanced splenic CD8+ T cell numbers in murine cytomegalovirus-infected mice. In contrast, high doses of IL-12 were detrimental to resistance against LCMV infection. Higher doses of IL-12: 1) inhibited virus-specific CTL lytic capacity per spleen by > 90%; 2) inhibited virus-induced expansion of CD8+ T cells in spleen, peripheral blood, and lymph nodes by > 80%; 3) induced necrotic lesions in splenic white pulp; and 4) resulted in 2 log increases in splenic and renal viral replication. Initiation of high dose IL-12 treatment on day 0, 1, 2, or 4 post-infection had similar effects. Although serum levels of IFN-gamma and TNF were normally not detectable in LCMV-infected mice, infection acted synergistically with IL-12 for cytokine induction. The IL-12-mediated reduction in CD8+ T cell numbers and synergistic enhancement of circulating cytokines levels observed during LCMV infection were unique to this infection. These results demonstrate that IL-12-mediated effects can be either protective or detrimental, depending upon the environment in which the factor is presented.
Orange
J S
JS
Division of Biology and Medicine, Brown University, Providence, RI 02912.
Wolf
S F
SF
Biron
C A
CA
D000818:Animals; D016827:CD8 Antigens / Q000032:analysis; D003586:Cytomegalovirus Infections / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D004305:Dose-Response Relationship, Drug; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12; D007378:Interleukins / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology; D008216:Lymphocytic Choriomeningitis / Q000276:immunology*; D008217:Lymphocytic choriomeningitis virus / Q000254:growth & development / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000166:cytology / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014779:Virus Replication / Q000187:drug effects
D016827:CD8 Antigens; D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma