The long-term objective of our research is to identify the mechanisms of conditioned tolerance. We have made the observation that tolerance to the natural killer (NK) cell stimulating effect of the nucleic acid polymer, poly I:C, is consistent with a conditioning analysis. We now wish to determine the mechanism of conditioned immunosuppression, and the locus of effect for the suppressive mechanism.
Our specific aims are to determine: 1) if conditioned tolerance occurs via the activation of ACTH and corticosterone production, and 2) if the conditioned immunosuppression occurs as a result of loss of interferon (IFN) responsiveness of the NK cell, or reduction in poly I:C Induced macrophage secretion of IFN and interleukin-1 (IL-1). We will first examine the conditioning of ACTH production to poly I:C and IL-1, assaying corticosterone release following multiple weekly pairings of the drug and conditioning cues. Evidence for conditioning will be sought using stimulus- specific extinction to attenuate the effects on corticosterone production. Extinction of tolerances by the same cues but not by cues which differ from those used in training is expected. Evidence of stimulus-specific latent inhibition will be sought, where cues will be pre-exposed to mice, examine the ability to retard acquisition of conditioning on corticosterone production. The final group of experiments will assess the locus of effect of tolerance to poly I:C by examining the loss of in vitro IFN responsiveness of the NK cell following tolerance training and its extinction and attenuation by latent inhibition. The alternative hypothesis that tolerance can occur via reduction of poly I:C effects on macrophage release of IFN and IL-1 will be evaluated by establishing macrophages in tissue culture from tolerant animals and assessing the release of IFN and IL-1 to poly I:C stimulation in vivo or in vitro. The role of glucocorticoids in abrogating poly I:C effects on macrophage release of these cytokines will test the hypothesis that glucocorticoid production, enhanced by conditioning, could reduce their release from stimulated macrophages. The effects of conditioned tolerance and glucocorticoids on IFN and IL-1 synthesis will also be tested both by bioassay and gene transcription by Northern blotting using specific cDNA probes. This is the first attempt to evaluate the role of a bidirectional immunoregulatory pathway acting via the CNS in a behavioral response.
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