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 ce ll-mediated immune response. To evaluate the effect of IL-12 on the co urse of influenza A virus infection, BALB/c mice were administered a d aily intraperitoneal dos 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. IFN gamma lung concentrations were 1193 +/- 275 p g/100 mu l in controls and 3693 +/- 745 pg/100 mu l in IL-12-treated m ice at day 5. IFN gamma levels were undetectable at day 13 in controls and 1335 +/- 220 pg/100 mu l in IL-12-rreated mice. Cytokine producti on was also assessed at the single-cell level for mediastinal lymph no des. IL-12 treatment increased the number of IL-2- and IFN gamma-produ cing cells and decreased the number of IL-4- and IL-10-producing cells . IL-12 treatment decreased the anti-influenza antibody response, espe cially anti-influenza IgG1 antibody resulting in an increased IgG2a/Ig G1 ratio. Primary pulmonary CTL activity on day 5 was low for both gro ups (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 diseas e. Following infection, control and IL-12-treated mice decreased their body weight to similar to 75% of their initial weight. After day 5, t he control mice started to recover, while IL-12-treated mice did not b egin recovering until day 9. Pulmonary viral titers were 1.6 +/- 0.3 T CID50 in controls at day 5 compared to 2.4 +/- 0.3 for IL-12-treated m ice (P < 0.01). In addition, control mice had significantly less sever e inflammation and damage on histologic examination. Serum TNF alpha c oncentrations, undetectable in control mice, were elevated by IL-12 tr eatment 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 induce s a switch from a Th2- to a Th1-mediated response, but inhibits recove ry probably through induction of TNF alpha. (C) 1998 Elsevier Science B.V. All rights reserved.