Differential Effects of Immunosuppressive Drugs on T‐Cell Motility

• Published in: American journal of transplantation Vol. 6; no. 12; pp. 2871 - 2883
• Main Authors: Datta, A., David, R., Glennie, S., Scott, D., Cernuda‐Morollon, E., Lechler, R. I., Ridley, A. J., Marelli‐Berg, F. M.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-12-2006; Blackwell
• Subjects: Animals; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - physiology; Cell Movement - drug effects; Chemokines - antagonists & inhibitors; Chemokines - physiology; Cyclosporin; Cyclosporine - pharmacology; Endothelium, Vascular - drug effects; Endothelium, Vascular - physiology; Everolimus; Fibronectins - physiology; Humans; Immunoblotting; Immunosuppressive Agents - pharmacology; Kinetics; Medical sciences; Mice; Mice, Inbred CBA; migration; Peritoneal Cavity; Pharmacology. Drug treatments; rapamycin; Sirolimus - analogs & derivatives; Sirolimus - pharmacology; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; T cells; T-Lymphocytes - immunology; T-Lymphocytes - physiology; Antineoplastic agent; Cyclosporin; Sirolimus; Migration; Lactone; T cells; Macrolide; Macrocycle; Cell motility; Antibiotic; T-Lymphocyte; Ciclosporin; Protein synthesis inhibitor; Immunosuppressive agent; Antibacterial agent; rapamycin
• ISSN: 1600-6135; 1600-6143
• DOI: 10.1111/j.1600-6143.2006.01553.x

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.
Cyclosporine has direct effects on the T cell motility and trans‐endothelial migration that could contribute to its ability to suppress T cell‐mediated inflammation.