title: Impact of small molecules immunosuppressants on P-glycoprotein activity and T-cell function.
abstract: OBJECTIVE
  P-glycoprotein (Pgp) is a member of the ABC-transporter family that transports substances across cellular membranes acting as an efflux pump extruding drugs out of the cells. Pgp plays a key role on the pharmacokinetics of several drugs. Herein, we have studied the effects of immunosuppressants on Pgp function, assessing rhodamine-123 (Rho123) uptake and efflux in different T-cell subsets.
  
  
  METHODS
  Different immunosuppressants such as Cyclosporine (CsA), Rapamycin (Rapa) and Tacrolimus (Tac) were used to assess the in vitro effect on Pgp function of main T-cell subsets among healthy volunteers. We measured Rho123 uptake, efflux and kinetic of extrusion in CD4+ and CD8+ subsets by flow cytometry. Antigen-specific memory T-cell responses were assessed by measuring T-cell proliferation and cytokine secretion using an allogeneic mixed lymphocyte reaction.
  
  
  RESULTS
  Rho123 uptake in groups treated with CsA and CsA+Rapa was significantly decreased compared to non-treated group and the other immunosupressants in both T cells subsets. Pgp activity was also reduced in CsA and CsA+Rapa compared to the other immunosupressants but it was only significant in the CsA group for CD8+ subset. Kinetic extrusion of Rho123 by Pgp in all groups was faster in CD8+ T cells. All immunosuppressants and the specific Pgp inhibitor PSC833 diminished antigen-primed T-cell proliferation, especially CD8+ T-cell subset.
  
  
  CONCLUSIONS
  Our data indicate that small molecules immunosuppressants, especially CsA, inhibit Pgp activity and T-cell function being the CD8+ T cells more susceptible to this effect. These findings support the importance of Pgp when designing combined immunosuppressive regimens.
authors.affiliation: Nephrology Department and Laboratory of Experimental Nephrology, Bellvitge University Hospital, Hospitalet de Llobregat, Spain. illaudo@ub.edu
authors.forename: Inés
authors.initials: I
authors.lastname: Llaudó
authors.forename: Linda
authors.initials: L
authors.lastname: Cassis
authors.forename: Joan
authors.initials: J
authors.lastname: Torras
authors.forename: Oriol
authors.initials: O
authors.lastname: Bestard
authors.forename: Marcel la
authors.initials: Ml
authors.lastname: Franquesa
authors.forename: Josep M
authors.initials: JM
authors.lastname: Cruzado
authors.forename: Gema
authors.initials: G
authors.lastname: Cerezo
authors.forename: Esther
authors.initials: E
authors.lastname: Castaño
authors.forename: Jordi
authors.initials: J
authors.lastname: Pétriz
authors.forename: Immaculada
authors.initials: I
authors.lastname: Herrero-Fresneda
authors.forename: Josep M
authors.initials: JM
authors.lastname: Grinyó
authors.forename: Núria
authors.initials: N
authors.lastname: Lloberas
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D020112:Rhodamine 123 / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000378:metabolism; D016559:Tacrolimus / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016207:Cytokines; D007166:Immunosuppressive Agents; D020112:Rhodamine 123; D016572:Cyclosporine; D020123:Sirolimus; D016559:Tacrolimus