THE EFFECTS OF ANDROSTENEDIOL AND DEHYDROEPIANDROSTERONE ON THE COURSE AND CYTOKINE PROFILE OF TUBERCULOSIS IN BALB C MICE/

Immunity to Mycobacterium tuberculosis requires a T helper 1 (Th1) cyt okine balance accompanied by tumour necrosis factor-alpha (TNF-alpha), and activated macrophages. These facets of the immune response are se nsitive to suppression by glucocorticoids (GC), which can reactivate a nd exacerbate tuberculosis in man and animals. Dehydroepiandrosterone (DHEA) and its derivative, 3 beta,17 beta androstenediol (AED), are re ported to have antiglucocorticoid properties in vivo. We therefore inv estigated the effects of predetermined optimal doses of these compound s, on the course of pulmonary tuberculosis in an established model in BALB/c mice in which an early phase of Th1-mediated response accompani ed by adrenal hyperplasia, is followed by a switch to Th2, progressive loss of TNF-alpha expression and disease progression. Both compounds were protective, particularly AED which caused a fall in bacterial cou nts and prolonged survival. These effects correlated with the appearan ce within 3 days of cellular infiltrates rich in cells expressing inte rleukin-2 (IL-2), IL-1 alpha and TNF-alpha, and with partial suppressi on of the switch to IL-4 producing cells that occurred in controls. AE D also caused enhanced development of granulomas at 14 days, and persi stence of granuloma formation to 120 days, with a corresponding suppre ssion of areas affected by pneumonia. Much of the therapeutic effect o f AED and DHEA was obtained by treating for only the first 3 weeks, wh ich is the phase of adrenal hyperplasia. These results suggest that th e ratio of GC to anti-CC steroids may play a role in the pathogenesis of tuberculosis, and Further investigation could lead to novel treatme nt strategies.