injections of egg albumin were administered to rats in association with audiovisual contextual cues (MacQueen, Marshall, Perdue, Siegel, & Bienenstock, 1989). Reexposure to the CS alone resulted in increased production of an enzyme (protease II) produced by rat mast cells that colonize the gastrointestinal tract. It remains to be determined whether this enzyme release was due to actions mediated by antigen- sensitized lymphocytes activated by the CS.
In the second study, Ader, Kelly, Moynihan, Grota, and Cohen (1993) exposed mice to repeated injections of a low, “physiologic” dose of the protein antigen keyhole limpet hemocyanin (ISLH). These repeated injections were always paired with a novel gustatory CS, chocolate milk. Measures of serum IgG antibody produced specifically against KLH revealed enhanced production of antibody when these animals were reexposed, on the test day, to the CS and a low suboptimal dose of antigen. This low dose of antigen only marginally elevated residual levels of KLH-specific IgG in conditioned animals that did not receive the CS; but in the presence of CS reexposure, it resulted in a marked stimulation of KLH-specific antibody production. Presentation of the CS in the absence of a low “booster” dose of KLH did not increase antigen-specific IgG, indicating that the CS alone does not have the capacity to induce B cells to produce antibody in the absence of actual antigen.
These latter results by Ader et al. (1993) demonstrate a conditioned enhancement of the antibody response of memory B lymphocytes to a specific antigen. The mechanisms underlying this effect have yet to be dissected but, as alluded to earlier, may include the various cytokines produced in response to immunogenic stimulation. In the case of antigen- stimulated cytokine production, it is possible that locally produced cytokines within regionally distinct lymph nodes may activate the CNS via afferent neuronal pathways, thereby forming the link between immune activation and perception of unique environmental cues.
This chapter has reviewed evidence showing that the inherent link between the immune system and the brain can be exploited through conditioning techniques. As discussed earlier, conditioning studies using immunosuppressive drugs suggest clinical applicability in situations where autoimmune diseases or clinical suppression of transplanted tissue is the desired goal. This is especially pertinent in light of the aversive properties of immunosuppressive therapy. Given what it is understood about the impact of stress on immune function (see Glaser & Kiecolt-Glaser, 1994), it is important to minimize the physical side effects of drug treatment. This will undoubtedly also reduce the psychological reaction to such side effects, and any further harm this may have on disease outcome.
The few studies demonstrating direct conditioning of the immune response using immunological stimulation as the UCS suggest possibilities for the optimization of the immunological effects of vaccines that are routinely given to ward off infectious illnesses (e.g., polio, tetanus, etc.). This can be done through the alignment of vaccination regimens with behavioral conditioning procedures. Alternatively, if further studies are carried out to understand the physiological mechanisms underlying direct conditioning of the immune response to antigen, it may be possible to manipulate these systems to optimize the development of immunological memory against various vaccines.
Finally, given that cytokines have been shown to modulate CNS function, it is important to learn how they may be involved in the development of conditioned antigen-specific immune responses. Moreover, the use of cytokines has been tested clinically on cancer patients, with some serious side effects, including neuroendocrine and neuropsychological alterations (Denicoff et al., 1989). Given that cytokines represent a potentially powerful tool for the treatment of cancer, it may be important to introduce behavioral strategies that can optimize the immunobiological effects of cytokine therapy while minimizing the physical and psychological side effects. However, further research is required to confirm its utility as an adjunct to traditional medical therapy.
This work was supported by PHS grant 51051 and the Pathology Education and Research Foundation.
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