Effect of metalloprotease inhibitors on corneal allograft survival.
OBJECTIVE
The expression of Fas ligand (FasL) in the cornea is essential for corneal allograft acceptance in mice. Because the expression of FasL on the surface of cells is sensitive to cleavage with matrix metalloproteases (MMPs), this study examined whether inhibitors of MMPs would lead to increased FasL expression and improved corneal allograft survival.


METHODS
Corneal endothelia derived from mice and humans were treated with MMP inhibitors, and FasL expression was examined. BALB/c mice were engrafted with C57BL/6 or C57BL/6-gld corneas and treated with an ointment containing the MMP inhibitor, doxycycline. Corneal allograft survival was monitored for 50 days.


RESULTS
Corneal endothelial cells from both mice and humans displayed increased surface expression of FasL after treatment with MMP inhibitors. The increase in surface expression was further evidenced by the ability of these cells to kill Fas-expressing target cells. Mice treated with doxycycline after corneal allograft transplantation showed significantly prolonged allograft survival and an increase in the overall acceptance rate.


CONCLUSIONS
MMP inhibitor treatment of cornea-derived endothelial cells results in increased FasL expression and function. MMP inhibitor treatment prolongs corneal allograft survival and results in a modest increase in corneal allograft acceptance.
Stuart
Patrick M
PM
Department of Ophthalmology, Washington University Medical School, St Louis, Missouri 63110, USA. stuart@vision.wustl.edu
Pan
Fan
F
Yin
Xiaotang
X
Haskova
Zdenka
Z
Plambeck
Stacey
S
Ferguson
Thomas A
TA
D000818:Animals; D002478:Cells, Cultured; D016039:Corneal Transplantation; D004151:Dipeptides / Q000494:pharmacology; D004318:Doxycycline / Q000494:pharmacology; D004728:Endothelium, Corneal / Q000187:drug effects / Q000378:metabolism; D053222:Fas Ligand Protein; D005260:Female; D005434:Flow Cytometry; D006085:Graft Survival / Q000187:drug effects*; D006801:Humans; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology*; D016038:Skin Transplantation; D013876:Thiophenes / Q000494:pharmacology; D014184:Transplantation, Homologous
D004151:Dipeptides; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; C075190:HSCH2CH(CH2CH(CH3)2)CO-Phe-Ala-NH2; D061965:Matrix Metalloproteinase Inhibitors; D008562:Membrane Glycoproteins; D011480:Protease Inhibitors; D013876:Thiophenes; D010649:Phenylalanine; C080985:batimastat; D004318:Doxycycline