Immunosuppressive activity of FK-506 in rats: flow cytometric analysis of lymphocyte populations in blood, spleen and thymus during treatment and following drug withdrawal.

Rats were immunized systemically with sheep red blood cells (SRBC) and given either FK-506 (1 mg/kg) or drug vehicle by i.m. injection for 7 days. In animals receiving FK-506, there was suppression (87%) of the splenic plaque-forming cell response on day 4 and marked reductions in the serum antibody titre throughout the 3-week period following immunization. Sequential flow cytometric analyses of blood lymphocytes revealed statistically significant attenuation, by FK-506, of the increase in relative numbers of OX-12+ (B) cells between days 4 and 7. Following drug withdrawal, OX-12 values remained elevated, whereas in control animals a decline was observed. These changes were reflected in concomitant increases in the relative numbers of OX-19+ (CD3+), W3/25+ (CD4+) and OX-8+ (CD8+) T cells; however, due to an overall reduction in lymphocytes by day 7, absolute values were not significantly affected compared with controls. The pattern of changes in OX-6+ (MHC class II+) cells in blood was similar to that observed for B cells. FK-506 also suppressed increases in the small proportion of blood-borne OX-40+ (activated CD4+) cells and OX-39+ (interleukin-2 receptor+) cells in the 7 day period following immunization; thereafter values for activation marker expression between treatment and control groups were similar. In the spleen, there were fewer significant differences between FK-506 and control groups in the incidences of cells expressing the above markers. OX-8+ cells, however, were significantly higher in drug-treated animals on day 7, and there were also reductions in the small proportions of OX-39+ and OX-40+ cells when compared with controls. In the thymus, reversible medullary atrophy induced by FK-506 was accompanied on day 7 by increases in the incidence of CD4+ and CD8+ cells and by a concomitant reduction in OX-44+ mature, medullary thymocytes. Two weeks after drug withdrawal, the phenotypic marker expression profile had been restored to normal in blood, spleen and thymus. These data provide new information on the apparent capacity of FK-506 to interfere with T cell maturation and its influence on lymphocyte activation in vivo.