EMERGENT IMMUNOREGULATORY PROPERTIES OF COMBINED GLUCOCORTICOID AND ANTI-GLUCOCORTICOID STEROIDS IN A MODEL OF TUBERCULOSIS

In Balb/c mice with pulmonary tuberculosis, there is a switch from a p rotective Th1-dominated cytokine profile to a non-protective profile w ith a Th2 component. This switch occurs while the adrenals are undergo ing marked hyperplasia. Treatment with the anti-glucocorticoid hormone s dehydroepiandrosterone or 3 beta, 17 beta-androstenediol, during the period of adrenal hyperplasia, maintains Th1 dominance and is protect ive. We investigated the effects of these hormones as therapeutic agen ts by administering them from day 60, when the switch to the non-prote ctive cytokine profile was already well established. Given at this tim e (day 60), doses that were protective when given early (from day 0) w ere rapidly fatal. A physiological dose of the glucocorticoid corticos terone was also rapidly fatal. However when the corticosterone and the anti-glucocorticoid (AED or DHEA) were co-administered, there was pro tection, with restoration of a Thf-dominated cytokine profile, enhance d DTH responses, and enhanced expression of IL-1 alpha and TNF alpha. Therefore this combination of steroids has an emergent property that i s quite unlike that of either type of steroid given alone. It may be p ossible to exploit the antiinflammatory properties of glucocorticoids while preserving a Th1 bias, by combining glucocorticoids with DHEA or suitable metabolites.