Abstract
Purpose :
Despite the advances in HLA matching and the use of immunosuppressive drugs, GVHD remains the most common and serious complication of allogeneic bone marrow transplantation. A large number of GVHD patients suffer from a severe form of dry eye which significantly impairs their visual health and quality of life. The pathogenesis of GVHD-dry eye has not been fully understood. The present study i) investigates the role of mucous layer dysfunction in the pathogenesis of GVHD dry eye ii) examines the beneficial effects of rebamipide, a mucin secretagouge, on GHHD dry eye.
Methods :
A GVHD mouse model of MHC Class I & II mismatch was used. B6D2F1 recipient mice were exposed to x-ray irradiation followed by retro-orbital injection of bone marrow and spleen cells obtained from C57B6 donor mice. The tear secretion was quantified every week using phenol red thread test. Corneal fluorescein staining was performed to detect epithelial defects. Cornea lysates and tears were used to measure mucins gene and protein expression by real-time PCR and ELISA. The corneal glycocalyx was stained using wheat germ agglutinin and imaged by confocal microscopy. The goblet cells staining was performed using periodic acid schiff stain. In a separate group of GVHD mice, the effect of 8 weeks topical ocular administration of either rebamipide or vehicle control eye drops was tested on tear secretion and corneal epithelial defects.
Results :
The MHC-mismatch murine model of GVHD caused a 3-fold decrease in tear secretion and a significant increase in corneal epithelial defects. These dry eye symptoms in GVHD mice were associated with a concomitant decrease in ocular surface glycocalyx. GVHD also caused a notable decrease in ocular surface mucins MUC1 and MUC4 but the results were significant only for MUC4. No effect was observed on MUC5AC and MUC16. GVHD also causes a noticeable decrease in goblet cell density. Topical administration of rebamipide was associated with a significant increase in tear secretion. Rebamipide also prevented the development of corneal epithelial defects and inhibited GVHD-associated decrease in ocular surface glycocalyx and goblet cell density.
Conclusions :
Alterations in ocular surface mucins may contribute to the pathogenesis of dry eye associated with GVHD and rebamipide, a mucins secretagouge, may an effective therapeutic approach to treat GVHD dry eye.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.