GLUCOCORTICOID RESISTANT ASTHMA - T-LYMPHOCYTE STEROID-METABOLISM ANDSENSITIVITY TO GLUCOCORTICOIDS AND IMMUNOSUPPRESSIVE AGENTS

We have previously shown that T-lymphocytes from clinically glucocorti coid (GC) resistant asthmatics are more refractory to dexamethasone su ppression in vitro than those of GC sensitive asthmatics, We wished to extend these observations to compare three GCs used topically for ast hma therapy (budesonide, beclomethasone dipropionate and fluticasone 1 7 alpha-propionate) and three immunosuppressive drugs (cyclosporin A, FK506 (tacrolimus) and mycophenolate mofetil) with dexamethasone for t heir antiproliferative effects on T-lymphocytes from GC sensitive and resistant asthmatics, and also to compare the rates of steroid metabol ism by T-lymphocytes from these patients. Antiproliferative activity o f the drugs was measured on peripheral blood T-lymphocytes activated w ith phytohaemagglutinin (PHA) and anti-CD3 antibody in vitro. The rate s of total steroid metabolism and 20 alpha-hydroxylation by T-cell hom ogenates were measured using radiolabelled progesterone as an establis hed probe substrate. Over a wide concentration range, T-lymphocytes fr om GC resistant asthmatics were significantly less inhibited by all fo ur GCs as compared with cells from GC sensitive asthmatics, The median inhibitory concentrations (IC50) for inhibition of T-lymphocytes from the GC resistant asthmatics exceeded those likely to be achieved ther apeutically by systemic administration (although higher concentrations might in theory be achieved locally in the bronchial mucosa by inhale d administration), In contrast, all three immunosuppressive drugs at p utative therapeutic concentrations inhibited T-lymphocytes both from G C sensitive and resistant asthmatics with equivalent potency, The rate s of total metabolism and 20 alpha-hydroxylation of steroid by homogen ates of T-lymphocytes from GC sensitive and resistant asthmatics were equivalent. Thus, relative GC resistance in T-lymphocytes from GC resi stant as compared with sensitive asthmatics is: 1) manifest with GC mo lecules of variable molecular structure; 2) not accompanied by elevate d intracellular metabolism of steroids; and 3) overcome by immunosuppr essive drugs which inhibit T-lymphocytes by non-CC-mediated mechanisms , We conclude that current anti-asthma glucocorticoids at therapeutic concentrations are unlikely to be of benefit for the therapy of glucoc orticoid resistant asthma, and that other immunosuppressive drugs may have potential as therapeutic agents in these patients.