In vivo suppression of major histocompatibility complex class II expression on porcine vascular endothelial cells by an HMG-CoA reductase inhibitor.
BACKGROUND
Vascular endothelial cells of man and pig, but not rodents, strongly express major histocompatibility complex (MHC) class II antigens in vivo, probably via the inducible promoter IV of the class II transactivator. There is abundant in vitro evidence that MHC class II positive vascular endothelial cells can activate T cells. Peripheral antigen presentation by endothelial cells is potentially important for organ-specific immunity, for allograft rejection, and possibly for immune responsiveness in general. Given the reported effects of statins on promoter IV of the class II transactivator, we evaluated in vivo expression of MHC class II antigens in pigs treated with atorvastatin calcium.


METHODS
Pigs were given 3 mg/kg/day of atorvastatin orally daily for 16 days, and then killed 24 hr after the last dose. Heart, kidney, and liver were removed for immunohistological and quantitative absorption analysis.


RESULTS
Double-labeling studies using immunofluorescence on frozen section for Factor VIII and MHC class II showed a marked suppression of MHC class II on vascular endothelial cells in all 4 treated pigs, in comparison with untreated pigs. This was confirmed using immunoperoxidase techniques on frozen sections. Quantitative absorption analysis showed up to 25-fold reduction in MHC class II expression.


CONCLUSIONS
Statins substantially suppress endothelial cell MHC class II expression in vivo. This is likely to inhibit organ-specific immune responses, and possibly also general immune responsiveness. In a transplantation setting, in addition to other regulatory effects on the recipients immune system, statins might reduce the long-term capacity of the donor organ to activate rejection mechanisms.
Department of Clinical Sciences, Guy's, King's & St. Thomas' School of Medicine, The Rayne Institute, King's Denmark Hill Campus, 123 Coldharbour Lane, London SE5 9NU, United Kingdom.
Ina
I
Geissler
Louise
L
Collins
Rebecca
R
Schofield
John W
JW
Fabre
D000818:Animals; D000069059:Atorvastatin; D042783:Endothelial Cells / Q000187:drug effects* / Q000276:immunology; D005455:Fluorescent Antibody Technique; D006538:Heptanoic Acids / Q000494:pharmacology*; D000949:Histocompatibility Antigens Class II / Q000032:analysis*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007124:Immunoenzyme Techniques; D008297:Male; D011758:Pyrroles / Q000494:pharmacology*; D013552:Swine
D006538:Heptanoic Acids; D000949:Histocompatibility Antigens Class II; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D000069059:Atorvastatin