Attenuation of graft arterial disease by manipulation of the LIGHT pathway.
OBJECTIVE
The tumor necrosis factor (TNF) superfamily member LIGHT, which binds herpes virus entry mediator (HVEM) and lymphotoxin beta receptor (LTbetaR), plays important roles in regulating the immune response. To clarify the mechanism underlying graft arterial disease (GAD), we investigated the role of the LIGHT pathway in the progression of GAD.


RESULTS
Hearts from Bm12 mice were transplanted into C57BL/6 (B/6) mice (class II mismatch). Recipients were injected intraperitoneally with HVEMIg (100 microg per treatment) every 7 days for 8 weeks. Treatment with HVEMIg significantly attenuated GAD (luminal occlusion=16.5+/-7.7% versus control allograft=62.6+/-12.1%, P<0.05), and significantly decreased intragraft IL-4, IL-6, and interferon-gamma (IFN-gamma) mRNA expression compared with controls. LTbetaR was expressed in smooth muscle cells (SMCs) with or without cytokine stimulation, whereas HVEM was detected in SMCs stimulated by IFN-gamma. Coculture of SMCs with T cells after transplantation induced SMC proliferation, and addition of HVEMIg resulted in inhibition of SMC proliferation.


CONCLUSIONS
These results indicate that the LIGHT pathway plays important roles in the regulation not only of T-cell activation but also of SMC proliferation. Blockade of the LIGHT pathway is a promising avenue for the prevention of GAD.
Kosuge
Hisanori
H
Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
Suzuki
Jun-ichi
J
Kakuta
Tsunekazu
T
Haraguchi
Go
G
Koga
Noritaka
N
Futamatsu
Hideki
H
Gotoh
Ryo
R
Inobe
Manabu
M
Isobe
Mitsuaki
M
Uede
Toshimitsu
T
D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology; D002455:Cell Division / Q000187:drug effects; D018920:Coculture Techniques; D003331:Coronary Vessels / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018076:DNA, Complementary / Q000235:genetics; D018450:Disease Progression; D006084:Graft Rejection / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control*; D016027:Heart Transplantation / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D015847:Interleukin-4 / Q000096:biosynthesis / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D008213:Lymphocyte Activation / Q000502:physiology; D053259:Lymphotoxin beta Receptor; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D009131:Muscle, Smooth, Vascular / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000502:physiology* / Q000627:therapeutic use; D053240:Receptors, Tumor Necrosis Factor, Member 14; D011991:Receptors, Virus / Q000235:genetics / Q000502:physiology* / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000627:therapeutic use*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous / Q000276:immunology*; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D018076:DNA, Complementary; D007074:Immunoglobulin G; D015850:Interleukin-6; C505697:LTBR protein, human; C505699:Ltbr protein, mouse; D053259:Lymphotoxin beta Receptor; D008565:Membrane Proteins; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D053240:Receptors, Tumor Necrosis Factor, Member 14; D011991:Receptors, Virus; D011993:Recombinant Fusion Proteins; C506028:TNFRSF14 protein, human; C505914:TNFSF14 protein, human; C506029:Tnfrsf14 protein, mouse; C505915:Tnfsf14 protein, mouse; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D007371:Interferon-gamma