Interleukin 12 administration enhances Th1 activity but delays recovery from influenza A virus infection in mice.
Interleukin 12 (IL-12) directs the differentiation of undifferentiated T helper (Th0) cells to T helper type 1 (Th1) cells and induces a cell-mediated immune response. To evaluate the effect of IL-12 on the course of influenza A virus infection, BALB/c mice were administered a daily intraperitoneal dose of 1000 ng of IL-12 or saline on days -1 to +4 for a total of six treatments. The treatment generally enhanced Th1-mediated responses. IFNgamma lung concentrations were 1193 +/- 275 pg/100 microl in controls and 3693 +/- 745 pg/100 microl in IL-12-treated mice at day 5. IFNgamma levels were undetectable at day 13 in controls and 1335 +/- 220 pg/100 microl in IL-12-treated mice. Cytokine production was also assessed at the single-cell level for mediastinal lymph nodes. IL-12 treatment increased the number of IL-2- and IFNgamma-producing cells and decreased the number of IL-4- and IL-10-producing cells. IL-12 treatment decreased the anti-influenza antibody response, especially anti-influenza IgG1 antibody resulting in an increased IgG2a/IgG1 ratio. Primary pulmonary CTL activity on day 5 was low for both groups (10% specific lysis). Secondary CTL activity at day 11 was higher for control mice than for IL-12-treated mice on day 11 (44 versus 34%), but not on day 13. Despite this overall enhancement of Th1-mediated immune functions, the IL-12 treatment increased severity of the disease. Following infection, control and IL-12-treated mice decreased their body weight to approximately 75% of their initial weight. After day 5, the control mice started to recover, while IL-12-treated mice did not begin recovering until day 9. Pulmonary viral titers were 1.6 +/- 0.3 TCID50 in controls at day 5 compared to 2.4 +/- 0.3 for IL-12-treated mice (P < 0.01). In addition, control mice had significantly less severe inflammation and damage on histologic examination. Serum TNFalpha concentrations, undetectable in control mice, were elevated by IL-12 treatment up to 80 pg/ml at day 5 and decreased to zero at day 13. It is concluded that IL-12 administration to influenza-infected mice induces a switch from a Th2- to a Th1-mediated response, but inhibits recovery probably through induction of TNFalpha.
Department of Pathology and Laboratory Medicine, University of Florida College of Medicine, Gainesville 32610-0275, USA.
S
S
Kostense
W H
WH
Sun
R
R
Cottey
S F
SF
Taylor
S
S
Harmeling
D
D
Zander
P A
PA
Small
B S
BS
Bender
D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D001835:Body Weight / Q000187:drug effects; D005260:Female; D007074:Immunoglobulin G / Q000378:metabolism; D007249:Inflammation; D009980:Influenza A virus / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000494:pharmacology* / Q000627:therapeutic use; D007378:Interleukins / Q000096:biosynthesis; D008168:Lung / Q000473:pathology / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D009976:Orthomyxoviridae Infections / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology / Q000821:virology; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D019562:Viral Load
D000914:Antibodies, Viral; D007074:Immunoglobulin G; D007378:Interleukins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma