SUMMARYInterleukin-13 ( IL-13) shares many, but not all, of the properties of the prototypic T-helper type 2 (Th2 ) cytokine IL-4, but its role in allergen-driven T-cell responses remains poorly defined. We hypothesized that allergen stimulation of peripheral blood T cells from patients with atopic disease compared with non-atopic controls results in elevated IL-13 synthesis in the context of a 'Th2-type' pattern. Freshly isolated peripheral blood mononuclear cells ( PBMC) obtained from sensitized atopic patients with allergic disease, and non-atopic control subjects, were cultured with the allergens Phleum pratense ( Timothy grass pollen) or Dermatophagoides pteronyssinus (house dust mite) and the non-allergenic recall antigen Mycobacterium tuberculosis purified protein derivative (PPD). Supernatant concentrations of IL-13, along with IL-5 and interferon-c ( IFN-c) ( Th2-and Th1-type cytokines, respectively) were determined by enzyme-linked immunosorbent assay ( ELISA). Allergen-induced IL-13 and IL-5 production by T cells from patients with allergic disease was markedly elevated (P=0·0075 and P=0·0004, respectively) compared with non-atopic controls, whereas IFN-c production was not significantly diÂerent. In contrast to allergen, the prototypic Th1-type antigen M. tuberculosis PPD induced an excess of IFN-c over IL-13 and IL-5 production, and absolute concentrations of cytokines were not aÂected by the presence or absence of atopic disease. Addition of exogenous recombinant IFN-c or IL-12, cytokines known to inhibit Th2-type responses, significantly inhibited allergen-driven production of both IL-13 and IL-5, but not T-cell proliferation, whereas exogenous IL-4 did not significantly aÂect production of IL-13 or IL-5. We conclude that allergen-specific T cells from atopic subjects secrete elevated quantities of IL-13 compared with non-atopic controls, in the context of a Th2-type pattern of cytokine production.

G Gl lu uc co oc co or rt ti ic co oi id d r re es si is st ta an nt t a as st th hm ma a: : T T--l ly ym mp ph ho oc cy yt te e s st te er ro oi id d m me et ta ab bo ol li is sm ma an nd d s se en ns si it ti iv vi it ty y t to o g gl lu uc co oc co or rt ti ic co oi id ds s a an nd d i im mm mu un no os su up pp pr re es ss si iv ve e a ag ge en nt ts s with dexamethasone for their antiproliferative effects on T-lymphocytes from GC sensitive and resistant asthmatics, and also to compare the rates of steroid metabolism by T-lymphocytes from these patients. Antiproliferative activity of the drugs was measured on peripheral blood T-lymphocytes activated with phytohaemagglutinin (PHA) and anti-CD3 antibody in vitro. The rates of total steroid metabolism and 20α-hydroxylation by T-cell homogenates were measured using radiolabelled progesterone as an established probe substrate.Over a wide concentration range, T-lymphocytes from GC resistant asthmatics were significantly less inhibited by all four 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 therapeutically by systemic administration (although higher concentrations might in theory be achieved locally in the bronchial mucosa by inhaled administration). In contrast, all three immunosuppressive drugs at putative therapeutic concentrations inhibited T-lymphocytes both from GC sensitive and resistant asthmatics with equivalent potency. The rates of total metabolism and 20α-hydroxylation of steroid by homogenates of T-lymphocytes from GC sensitive and resistant asthmatics were equivalent.Thus, relative GC resistance in T-lymphocytes from GC resistant as compared with sensitive asthmatics is: 1) manifest with GC molecules of variable molecular structure; 2) not accompanied by elevated intracellular metabolism of steroids; and 3) overcome by immunosuppressive drugs which inhibit T-lymphocytes by non-GC-mediated mechanisms. We conclude that current anti-asthma glucocorticoids at therapeutic concentrations are unlikely to be of benefit for the therapy of glucocorticoid resistant asthma, and that other immunosuppressive drugs may have potential as therapeutic agents in these patients.