Costimulatory signal confers steroid resistance on human helper T cells

Costimulatory signal confers steroid resistance on human helper T cells

S48 Abstracts SATURDAY 89 Costimulatory Signal Confers Steroid Resistance on Human Helper T Cells A. Mori, T. Hashimoto, K. Akiyama; Clinical Resea...

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S48 Abstracts

SATURDAY 89

Costimulatory Signal Confers Steroid Resistance on Human Helper T Cells

A. Mori, T. Hashimoto, K. Akiyama; Clinical Research Center, National Sagamihara Hospital, Sagamihara, JAPAN. RATIONALE: Helper T (Th) cells and T cell cytokines, including especially IL-5, have been implicated in the pathogenesis of asthma. To investigate the mechanisms of steroid-dependent asthma, effect of glucocorticoids on T cell proliferation and cytokine synthesis was examined. METHODS: Peripheral blood mononuclear cells (PBMC) were prepared from mild, steroid-dependent (SD), steroid-resistant (SR) asthma patients, and healthy subjects. CD4+ T cells were purified from PBMC. Th clones were established by stimulating PBMC with mite allergens, followed by the limiting dilution. Cells were stimulated by anti-CD3 with or without anti-CD28 in the presence of various concentrations of glucocorticoids, and inhibitory action on their proliferation and cytokine production was assessed. IC50 values were calculated from the dose-response curves. Dendritic cells (DC) were obtained from PBMC cultured with IL-4 and GM-CSF, and added to some cultures. RESULTS: IL-5 production by PBMC of mild asthma decreased after commencement of inhaled steroids, but that of SD asthma remained at high levels. IC50 on the cytokine synthesis and proliferation was not statistically different among the donor groups. Costimulation by CD28 antibody increased IC50 on IL-5 synthesis by 3 times, and that on proliferation by more than 100 times. Coculture with DC showed the same effects. Reduced or loss of the glucocorticoid sensitivity was dependent on secreted IL-2. CONCLUSIONS: Relative unresponsiveness of SD asthma T cells to glucocorticoid action may be induced by the provision of costimulatory signals in vivo. Funding: Ministry of Health, Labour, and Welfare

J ALLERGY CLIN IMMUNOL FEBRUARY 2004