THE ROLE OF CHEMICAL-INDUCED STRESS RESPONSES IN IMMUNOSUPPRESSION - A REVIEW OF QUANTITATIVE ASSOCIATIONS AND CAUSE-EFFECT RELATIONSHIPS BETWEEN CHEMICAL-INDUCED STRESS RESPONSES AND IMMUNOSUPPRESSION

Although there is an increasing awareness that drugs and chemicals can modulate the immune system by indirect mechanisms, few compounds have been thoroughly evaluated in this regard. Several environmentally rel evant chemicals induce stresslike responses, as indicated by elevated glucocorticoid levels. Comparable glucocorticoid levels induced by phy sical or psychological stressors are consistently associated with supp ression of one or more immunological parameters. Thus, it seems likely that stress-related neuroendocrine mechanisms are important in immuno suppression by some environmental chemicals. Distinguishing direct and indirect (stress-related) mechanisms of immunosuppression is generall y possible, and this could be done as a routine part of immunotoxicity assessment. Although it is clear that glucocorticoids can contribute to such immunosuppression, it is also clear that several other neuroen docrine mediators associated with stress responses can be immunomodula tory. Thus, correlation between glucocorticoid levels and immunosuppre ssion does not conclusively demonstrate a cause-effect relationship. D emonstrating such relationships has been difficult, but it has been do ne in a few cases of drug-induced thymic hypoplasia by monitoring seve ral parameters known to be affected by glucocorticoids and by measurin g the ability of a glucocorticoid antagonist (RU 486) or adrenalectomy to block changes in these parameters. A similar strategy might be use ful for evaluation of the role of glucocorticoids in drug- or chemical -induced suppression of a variety of immune functions, but the effects of RU 486 on neuroendocrine feedback circuits and the possibility of consequent immunological changes must be considered when the data are interpreted This approach could also be applied to evaluation of the r oles in chemical-induced immunosuppression of other neuroendocrine med iators for which antagonists or agents that block the synthesis or rel ease of the mediator are available. However, it is likely that a compr ehensive (and perhaps predictive) understanding of the relationship be tween chemically induced stress responses and immunosuppression will r equire more detailed and quantitative elucidation of the mechanisms an d regulation of neuroendocrine-immune interactions.