The effects of corticosteroids on lymphocyte recirculation in humans: analysis of the mechanism of impaired lymphocyte migration to lymph node following methylprednisolone administration.
BACKGROUND
Steroid therapy profoundly inhibits lymphocyte migration into lymph nodes (LN), thereby disrupting lymphocyte recirculation. This study was undertaken in human subjects to examine two nonmutually exclusive hypotheses proposed to explain this steroid effect: (1) steroids decrease the capacity of LN high endothelial venules (HEV) to support lymphocyte adherence; and/or (2) steroids alter the expression of lymphocyte adhesion molecules specific for entry into LNs.


METHODS
Human LNs were obtained from cadaveric organ donors before and after methylprednisolone infusion and examined for their capacity to support lymphocyte adherence using an in vitro lymphocyte-HEV adherence assay. Additionally, six healthy volunteers underwent infusions of saline (placebo) and methylprednisolone (3 mg/kg in saline), and peripheral blood lymphocytes were isolated before, immediately after, and at 1, 2, 4, 8, 24, and 48 hours following infusions. At each timepoint, flow cytometric analysis of lymphocyte L-selectin, CD44, and LFA-1 expression was assessed. Short-term tissue culture studies were also performed to examine the direct effects of steroids on the expression of these lymphocyte proteins.


RESULTS
LNs obtained from organ donors before and after steroid infusion displayed no differences in the capacity of HEV to support lymphocyte adherence. In controlled steroid infusion studies, lymphopenia was observed within 1 hour and persisted for 8 hours. Cells isolated during the period of lymphopenia did not adhere to LN HEV, and there was a marked decrease in both the percentage and mean fluorescence intensity level of L-selectin+ lymphocytes; minor changes were observed in the percentage of CD44+ and LFA-1+ cells, while the mean fluorescence intensity level decreased for CD44+ cells and increased for LFA-1+ cells. All such changes in adhesion protein levels among circulating cells reversed with the resolution of lymphopenia. However, in tissue culture experiments, steroids did not alter the expression of lymphocyte adhesion proteins.


CONCLUSIONS
The decreased migration of lymphocytes to LN following steroid administration is not due to changes in the capacity of HEV to bind lymphocytes, but results from decreases in the level of L-selectin expressed among circulating cells. Culture studies suggest that steroids do not directly alter lymphocyte adhesion protein expression. The possibility that these agents act indirectly by stimulating the release and/or promoting the activity of relevant biologic mediators affecting lymphocyte adhesion protein expression needs further exploration.
Sackstein
R
R
Miami Veterans Affairs Medical Center, Department of Medicine, FL, USA.
Borenstein
M
M
D000328:Adult; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D004727:Endothelium / Q000166:cytology; D005260:Female; D006801:Humans; D008198:Lymph Nodes / Q000166:cytology*; D018655:Lymphocyte Count / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008775:Methylprednisolone / Q000494:pharmacology*
D008775:Methylprednisolone