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(Investigative Ophthalmology and Visual Science. 2004;45:1169-1173.)
© 2004 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.03-0932
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Effect of Metalloprotease Inhibitors on Corneal Allograft Survival

Patrick M. Stuart,1,2 Fan Pan,1 Xiaotang Yin,1 Zdenka Haskova,1,3 Stacey Plambeck,1 and Thomas A. Ferguson1

1From the Department of Ophthalmology and Visual Sciences and 2Molecular Microbiology and Pathogenesis, Washington University Medical School, St. Louis, Missouri; and the 3Transplantation Research Center, Harvard Medical School, Boston, Massachusetts.

PURPOSE. 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.






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Copyright © 2004 by the Association for Research in Vision and Ophthalmology