Cyclosporine Inhibition ofCalcineurin Activity inHumanLeukocytes InVivo isRapidly Reversible
1995
Despite increasing information aboutthemechanism ofaction ofcyclosporine A (CsA), little isknownabouttheway lymphocytes recover fromCsA.Recovery iscentral tounderstanding thepharmacodynamics ofCsAinvivo. We studied therecovery ofcalcineurin phosphatase (CN)activityinCsA-treated cells. Single dosekinetics inrenal transplant patients showedthatinhibition ofCN activity inPBL increased andfell concomitant withCsAbloodlevels. In vitro, control PBLtreated withCsA100pg/l, washed, and resuspended inCsA-free mediumshowed little recovery (020%)after 24h.Erythrocytes oranti-CsA Abaddedtothe recovery mediumincreased recovery to50% within 4h. Similar recovery wasseenintheability ofcells toproduce IFN-'y after OKT3stimulation. Recovery ofCNactivity was associated withtheefflux of[3H]CsA, wasnotblocked by cycloheximide andwastemperature sensitive. A cell line withhighexpression ofsurface P glycoprotein (PGP), showedrapid recovery. However, PGP blockade didnot prevent recovery inPBL,indicating adifferent PGP-independent mechanism. InPBL,recovery fromCsAisslow andlimited invitro, butrapid invivo, whereCsAequilibrates amongacomplex setofextralymphocytic binding sites. (J.Clin. Invest. 1995. 96:1254-1260.) Kewwords: Pglycoprotein * transplantation * immunosuppression cyclophilin *rejection
Keywords:
- Correction
- Cite
- Save
- Machine Reading By IdeaReader
8
References
0
Citations
NaN
KQI