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NK CeU Activity Inhibited by Orally Administered Theophylline The direct addition of more than 5x 10 aminophylline significantly inhibited NK cell activity in vitro. Since aminophylline contains two molecules of theophylline per one molecule, this is the maximum therapeutic concentration. Furthermore, NK cell activity of preincubated PBLs was also inhibited. Those in vitro effects suggested that theophylline may inhibit the NK cell activity at therapeutic concentrations (5iig/ml to 20iig/ml; 2.2 to llxl0_5M) in vivo. To test this possibility, we administered sustained-release theophylline to five healthy volunteers. The protocol is described in the methods section. As shown in Figure 2A, NK cell activity was significantly decreased compared to that before administration (p<0.01). The mean percentage of inhibition was 41.3 percent (range, 26.5 to 53.0 percent). No major side effects were observed. The serum concentrations of theophylline yielded a mean value of 2.0 x 10~M (range, 1.4 to 3.3 X 10-5M). These concentrations were markedly lower than those yielding the same inhibition in direct-addition experiments in vitro (Fig 3). Figure 2. A (left): NK cell activity was inhibited by oral administration of theophylline; NK cell activity was assessed before, after, and seven days after cessation of administration of theophylline. Significant inhibition was observed after administration (mean, 41.3 percent inhibition) and returned to original level by seven days after administration; p value was calculated by paired f-test. B (right): NK cell activity following administration was also inhibited even in presence of IL-2; NK cell activity was assessed in presence of IL-2 (100 units/ml). Responsiveness to IL-2 was retained but significantly (p<0.01; paired t-test) inhibited in comparison with that before administration. Numbers of subjects denote same persons as Figure 2A. Figure 3. Degree of inhibition was greater than expected from results in vitro. Relationship between concentration of aminophylline (expressed as theophylline concentrations) and percentage of inhibition in vitro was plotted (open circles with solid line). Data from each volunteer were also shown (solid circles). Serum concentrations after administration in vivo gave mean value of 2.0 x 10~M, which was much lower than concentration yielding same inhibition in vitro (about 20 X 10_5M).