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.
Department of Pathology, University of Aberdeen, Scotland.
J
J
Woo
D J
DJ
Propper
A M
AM
Macleod
A W
AW
Thomson
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D001402:B-Lymphocytes / Q000276:immunology; D001803:Blood Transfusion; D015704:CD4 Antigens / Q000096:biosynthesis; D016827:CD8 Antigens; D003524:Cyclosporins / Q000494:pharmacology*; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007518:Isoantibodies / Q000096:biosynthesis*; D008213:Lymphocyte Activation / Q000187:drug effects*; D051381:Rats; D011919:Rats, Inbred Strains; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D013154:Spleen / Q000276:immunology; D016559:Tacrolimus
D000900:Anti-Bacterial Agents; D000945:Antigens, Differentiation, T-Lymphocyte; D015704:CD4 Antigens; D016827:CD8 Antigens; D003524:Cyclosporins; D000949:Histocompatibility Antigens Class II; D007166:Immunosuppressive Agents; D007518:Isoantibodies; D015375:Receptors, Interleukin-2; D016559:Tacrolimus