Suppression of neointimal hyperplasia after vascular injury by blocking 4-1BB/4-1BB ligand pathway.
OBJECTIVE
T cell-mediated immunity is involved in the pathogenesis of atherosclerosis and arteriosclerosis. This study examined whether the 4-1BB pathway affects the development of arteriosclerosis after vascular injury.


RESULTS
The left or right femoral arteries of adult male mice weighing 22 to 25 g were injured with a straight spring wire. The injured artery was excised 28 days later. Confocal microscopy revealed intense expression of both 4-1BB and 4-1BBL in the developing neointima and media. Similar results were obtained on immunoblotting analysis of lysates of the injured arteries. We gave mice an injection of 100 microg or 200 microg 4-1BB-fused with human immunoglobulin (Ig) every other day over the course of 5 days. As compared with untreated controls (intima/media ratio, 2.13 +/- 0.37, n=10), the intima/media ratio was smaller in mice treated with 200 microg of 4-1BBIg (1.20 +/- 0.30, n=6, p<0.05), but not in mice treated with 100 microg of 4-1BBIg (1.56 +/- 0.27, n=9).


CONCLUSIONS
4-1BB inhibits neointimal hyperplasia after vascular injury. Our findings suggest that 4-1BB is involved in injury-induced neointimal hyperplasia and may be an effective target for the treatment of neointimal hyperplasia.
Karube
Akiyo
A
Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
Suzuki
Jun-ichi
J
Haraguchi
Go
G
Maejima
Yasuhiro
Y
Saiki
Hitoshi
H
Kosuge
Hisanori
H
Isobe
Mitsuaki
M
Uede
Toshimitsu
T
D053330:4-1BB Ligand / Q000032:analysis / Q000037:antagonists & inhibitors*; D000199:Actins / Q000032:analysis; D000818:Animals; D001161:Arteriosclerosis / Q000517:prevention & control; D004195:Disease Models, Animal; D005263:Femoral Artery / Q000187:drug effects / Q000293:injuries* / Q000473:pathology; D019085:Fluorescent Antibody Technique, Direct; D006801:Humans; D006965:Hyperplasia; D007074:Immunoglobulin G; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018613:Microscopy, Confocal; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000473:pathology; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000032:analysis / Q000037:antagonists & inhibitors*; D017539:Tunica Intima / Q000187:drug effects / Q000293:injuries* / Q000473:pathology; D017540:Tunica Media / Q000473:pathology
D053330:4-1BB Ligand; D000199:Actins; D007074:Immunoglobulin G; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9