Inter- and intra-subject variation of the suppression of mitogen-induced proliferation of human lymphocytes by cyclosporin-A: reduction of response with delayed addition may be relevant to timing of therapy.
In vitro, CsA is capable of suppressing mitogen-stimulated growth of human peripheral blood lymphocytes. Dose--response studies on lymphocytes from normal volunteers have shown that the variation between subjects is greater than the variation between repeated studies on the same subject in the 72 h uptake of 3H-TdR. The tests are easy to perform and they could be used to help in deciding, prior to transplantation, the dose of CsA to be used and whether other immunosuppressive therapy is needed. Activation of lymphocyte proliferation in vivo is a continuous process and recruitment to growth in vitro takes place over 24 h after mitogen stimulation. CsA was most effective in suppressing the replicative growth of lymphocytes in vitro when added up to 4 h after the start of the culture, but it was much less effective when added at 8 h. The experiments suggest that 8 hourly administration of CsA will optimise suppression of activation of the lymphocytes in vivo. If the suppressive activity of the metabolite M17 and the individual variation in sensitivity of the patients' lymphocytes to CsA are also taken into account it may be possible to reduce the dose of CsA to achieve effective immunosuppression and thereby minimise toxicity.
Spiers
E M
EM
Department of Pathology, University of Dundee, Ninewells Hospital and Medical School, U.K.
Beck
J S
JS
D003524:Cyclosporins / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D006801:Humans; D066298:In Vitro Techniques; D008213:Lymphocyte Activation / Q000187:drug effects*; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010835:Phytohemagglutinins / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism; D013997:Time Factors
D003524:Cyclosporins; D010835:Phytohemagglutinins; D013936:Thymidine