Emergent immunoregulatory properties of combined glucocorticoid and anti-glucocorticoid steroids in a model of tuberculosis

Abstract

In Balb/c mice with pulmonary tuberculosis, there is a switch from a protective Th1-dominated cytokine profile to a non-protective profile with a Th2 component. This switch occurs while the adrenals are undergoing marked hyperplasia. Treatment with the anti-glucocorticoid hormones dehydroepiandrosterone or 3β, 17β-androstenediol, during the period of adrenal hyperplasia, maintains Th1 dominance and is protective. We investigated the effects of these hormones as therapeutic agents by administering them from day 60, when the switch to the non-protective cytokine profile was already well established. Given at this time (day 60), doses that were protective when given early (from day 0) were rapidly fatal. A physiological dose of the glucocorticoid corticosterone was also rapidly fatal. However when the corticosterone and the anti-glucocorticoid (AED or DHEA) were co-administered, there was protection, with restoration of a Th1-dominated cytokine profile, enhanced DTH responses, and enhanced expression of IL-1α and TNFα. Therefore this combination of steroids has an emergent property that is quite unlike that of either type of steroid given alone. It may be possible to exploit the antiinflammatory properties of glucocorticoids while preserving a Th1 bias, by combining glucocorticoids with DHEA or suitable metabolites.