Tolerance to drug-induced (poly I:C) natural killer cell activation: congruence with a Pavlovian conditioning model

Two experiments were conducted to assess the role of conditioning factors on the tolerance of drug-induced natural killer (NK) cell activity. A protocol in which mice were given four weekly injections of the immunostimulatory synthetic polynucleotide (poly I:C) paired with a complex environmental stimulus produced a reliable tolerance effect. The sensitivity of the observed tolerance to known decremental conditioning procedures--extinction (Experiment 1) and preexposure to the conditioning stimulus (latent inhibition, Experiment 2)--was investigated. The results indicated that posttreatment exposure to drug-signaling cues (i.e., extinction) significantly reversed tolerance such that NK cell activity was at a level comparable to that for controls receiving the drug for the first time (Experiment 1). In a similar fashion, pretreatment exposure to the drug-signaling cues (CS preexposure) inhibited the development of tolerance (Experiment 2). These results provide initial evidence that nonpharmacological manipulations of drug-signaling environmental cues can affect tolerance to the immunostimulatory effect of poly I:C, as would be expected with a conditioning analysis of such tolerance.