Statins inhibit lymphocyte homing to peripheral lymph nodes.
Lymphocyte homing to peripheral lymph nodes is governed by adhesion molecules, including lymphocyte function-associated antigen 1 (LFA-1). Statins are 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors and exert anti-inflammatory effects, e.g. inhibition of LFA-1. It is still not known whether statin compounds are capable of inhibiting lymphocyte homing in vivo. We used a cervical lymph node preparation to study the effects of simvastatin on lymphocyte adhesion to high endothelial venules (HEVs) by means of intravital fluorescence microscopy (IVM). IVM revealed that firm adhesion of lymphocytes to HEV endothelium critically depends on the adhesive function of LFA-1. The number of firmly adherent lymphocytes was reduced by 58% in LFA-1-deficient mice (P < 0.05 versus wild-type controls). As in mutant mice, acute treatment with simvastatin (i.p. injection at 2 hr prior to IVM) inhibited the firm adhesion of lymphocytes to HEV endothelium of wild-type animals by 63% (P < 0.05 versus vehicle-treated wild-type controls). In addition, acute treatment with the synthetic statin-derivate LFA878 also reduced firm lymphocyte adhesion in HEVs by 63% (P > 0.05 versus placebo-treated controls). Histological analysis after a 10-day treatment with simvastatin showed reduced cellularity of cervical lymph nodes, as indicated by a reduction of the relative area of haematoxylin-stained cell nuclei in cervical lymph node cross-sections from 94 +/- 0% in vehicle-treated controls to 77 +/- 3% in simvastatin-treated mice (P < 0.05). We conclude that statin compounds are capable of inhibiting lymphocyte homing to murine peripheral lymph nodes in vivo. This may have novel implications for the treatment of adaptive immune responses, e.g. transplant rejection.
Schramm
René
R
Department of Thoracic and Cardiovascular Surgery, University of Saarland, University Hospitals Homburg/Saar, Germany. reneschramm@hotmail.com
Menger
Michael D
MD
Harder
Yves
Y
Schmits
Rudolf
R
Adam
Oliver
O
Weitz-Schmidt
Gabriele
G
Schäfers
Hans-Joachim
HJ
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007958:Leukocyte Count; D036904:Leukocyte Rolling / Q000187:drug effects*; D008198:Lymph Nodes / Q000276:immunology*; D042601:Lymphatic Vessels / Q000276:immunology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology; D008214:Lymphocytes / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D009281:Naphthalenes / Q000494:pharmacology; D009333:Neck; D010078:Oxazines / Q000494:pharmacology; D019821:Simvastatin / Q000494:pharmacology
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C494439:LFA 878; D016169:Lymphocyte Function-Associated Antigen-1; D009281:Naphthalenes; D010078:Oxazines; D019821:Simvastatin