Modulation of integrin alpha4beta1 (VLA-4) in dry eye disease.
OBJECTIVE
To study the effect of topical application of very late antigen 4 (VLA-4) small-molecule antagonist (anti-VLA-4 sm) in a mouse model of dry eye disease.


METHODS
Anti-VLA-4 sm (or control vehicle) was applied topically to mice placed in a controlled-environment chamber. Corneal fluorescein staining and conjunctival T-cell enumeration were performed in the different treatment groups. Real-time polymerase chain reaction was used to quantify expression of inflammatory cytokines in the cornea and conjunctiva.


RESULTS
Dry eye syndrome induced increased corneal fluorescein staining, corneal and conjunctival tumor necrosis factor alpha messenger RNA expression, and T-cell infiltration into the conjunctiva. Very late antigen 4 blockade significantly decreased corneal fluorescein staining compared with the untreated dry eye disease and control vehicle-treated groups (P < .001 and P = .02, respectively). In addition, VLA-4 blockade was associated with a significant decrease in conjunctival T-cell numbers (P < .001 vs control vehicle-treated group) and tumor necrosis factor-alpha transcript levels in the cornea (P = .04 vs control vehicle-treated group) and conjunctiva (P = .048 vs control vehicle-treated group).


CONCLUSIONS
Application of topical anti-VLA-4 sm led to a significant decrease in dry eye signs and suppression of inflammatory changes at the cellular and molecular levels.


CONCLUSIONS
Topical blockade of VLA-4 may be a novel therapeutic approach to treat the clinical signs and inflammatory changes accompanying dry eye disease.
Ecoiffier
Tatiana
T
Schepens Eye Research Institute, Harvard Medical School, Boston, MA 02114, USA.
El Annan
Jaafar
J
Rashid
Saadia
S
Schaumberg
Debra
D
Dana
Reza
R
D000287:Administration, Topical; D000818:Animals; D017252:CD3 Complex / Q000378:metabolism; D019013:CD40 Antigens / Q000235:genetics; D054357:Chemokine CXCL10; D003228:Conjunctiva / Q000378:metabolism; D003315:Cornea / Q000378:metabolism; D016207:Cytokines / Q000235:genetics; D004195:Disease Models, Animal; D015352:Dry Eye Syndromes / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D005260:Female; D019793:Fluorescein / Q000378:metabolism; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D010671:Phenylurea Compounds / Q000737:chemistry / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000737:chemistry; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics
C475231:2-((1-(3,5-dichlorobenzenesulfonyl)pyrrolidine-2-carbonyl)amino)-4-(4-methyl-2-(methyl-(2-(4-(3-o-tolylureido)phenyl)acetyl)amino)pentanoylamino)butyric acid; D017252:CD3 Complex; D019013:CD40 Antigens; D054357:Chemokine CXCL10; D016207:Cytokines; D039041:Integrin alpha4beta1; D009842:Oligopeptides; D010671:Phenylurea Compounds; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D011092:Polyethylene Glycols; D019793:Fluorescein