Influence of FK506 and Cyclosporin A on Alloantibody Production and Lymphocyte Activation Following Blood Transfusion

The effect of administration of cyclosporin A (CyA) or the novel macrolide FK506 was investigated in AO rats given DA blood transfusions. CyA (10 mg/kg, orally) or FK506 (1 mg/kg, intramuscularly) administered for 14 days from the time of transfusion effectively inhibited primary anti-MHC class I alloantibody production. This profound inhibitory effect persisted throughout the 2-month investigation period, with little increase in 'secondary' alloantibody production following a challenge injection 28 days after drug withdrawal. Flow cytometric analysis revealed no significant differences in the absolute numbers of W3/25+ (CD4+), OX-8+ (CD8+) or OX-12+ (B lymphocytes), in either the spleen or peripheral blood of transfused compared with normal, untreated animals. However, a small but significant increase in the numbers of splenocytes expressing the activation marker OX-40 (activated CD4+ cells) was observed in transfused animals. Either CyA or FK506 significantly reduced the number of cells expressing OX-39 (interleukin-2 receptors) and OX-40. Treatment of transfused animals with CyA, but not FK506 for 14 days resulted in minor, transient reduction in peripheral blood OX-19+ and W3/25+ cells, while 'sparing' the OX-8+ cells; these changes were not observed in spleens. In contrast, the absolute spleen cell numbers of OX-19+, W3/25+ and OX-8+ cells were significantly reduced in transfused animals given 14 days of FK506 treatment, while the corresponding blood cells were unaffected. Induction of splenic lymphoproliferative responses by the T cell mitogen concanavalin A remained normal in animals receiving transfusion alone or with CyA. In contrast, profound inhibition of mitogenic responses was observed in FK506-treated animals and this inhibitory effect declined gradually following drug withdrawal. No non-specific suppressor cell activity was detected in the spleens of rats given transfusion alone or in CyA or FK506-treated transfused animals.