Differential effects of immunosuppressive drugs on T-cell motility.
The best-characterized mechanism of the action of immunosuppressive drugs is to prevent T-cell clonal expansion, thus containing the magnitude of the ensuing immune response. As T-cell recruitment to the inflammatory site is another key step in the development of T-cell-mediated inflammation, we analyzed and compared the effects of two commonly used immunosuppressants, cyclosporin A (CsA) and the rapamycin-related compound SDZ-RAD, on the motility of human CD4+ T cells. We show that CsA, but not SDZ-RAD, inhibits T-cell transendothelial migration in vitro. CsA selectively impaired chemokine-induced T-cell chemotaxis while integrin-mediated migration was unaffected. The inhibition of T-cell chemotaxis correlated with reduced AKT/PKB but not ERK activation following exposure to the chemokine CXCL-12/SDF-1. In addition, CsA, but not SDZ-RAD, prevents some T-cell receptor-mediated effects on T-cell motility. Finally, we show that CsA, but not SDZ-RAD inhibits tissue infiltration by T cells in vivo. Our data suggest a prominent antiinflammatory role for CsA in T-cell-mediated tissue damage, by inhibiting T-cell trafficking into tissues in addition to containing clonal expansion.
Datta
A
A
Department of Immunology, Division of Medicine, Imperial College London, Hammersmith Hospital Campus, London, UK.
David
R
R
Glennie
S
S
Scott
D
D
Cernuda-Morollon
E
E
Lechler
R I
RI
Ridley
A J
AJ
Marelli-Berg
F M
FM
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects*; D018925:Chemokines / Q000037:antagonists & inhibitors / Q000502:physiology; D016572:Cyclosporine / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D000068338:Everolimus; D005353:Fibronectins / Q000502:physiology; D006801:Humans; D015151:Immunoblotting; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007700:Kinetics; D051379:Mice; D008808:Mice, Inbred CBA; D010529:Peritoneal Cavity; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology*
D018925:Chemokines; D005353:Fibronectins; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D000068338:Everolimus; D020123:Sirolimus