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Samantha Herretes, Duncan Ross, Jose Echegaray, Nicholas J. Cutrufello, Robert Levy, Victor L. Perez; Dry Eye and Ocular Surface Changes in Murine Graft-versus-Host Disease. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2336.
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Allogeneic hematopoietic stem cell transplantation is a potentially curative therapy for hematologic malignancies but is complicated by the occurrence of Graft-versus-host disease (GVHD). Patients with GVHD frequently present with severe ocular surface disease and dry eye, potentially causing vision loss. We examined the in vivo corneal changes in a clinically relevant minor-mismatch bone marrow (BM) transplantation model of GVHD.
After high-dose total body irradiation (10.5 cGy), C3H.SW mice received BM transplantation from C57BL/6 (B6) donors. Mice were divided into 4 groups based upon the inoculum and treatment received: (1) T-cell depleted BM; (2) BM + CD4+/CD8+ T-cells; (3) BM + T-cells + Cyclophosphamide 11mg/kg x2; (4) BM + T-cells + Cyclophosphamide 33mg/kg x2. Weights were assessed weekly and GVHD was clinically scored according to the method of Cooke et al. Dry eye was evaluated weekly by measuring tear fluid production (mm of phenol red cotton thread wetting) and corneal surface staining with fluorescein (score from 0-15). Mice were euthanized at 6-7 wks, and corneal histology with hematoxilin/eosin staining was performed.
Mice that received T-cells and no treatment developed evidence of systemic GVHD by day 15. This group trended toward reduced tear fluid production when compared to the control and cyclophosphamide-treated groups. Beginning at day 21, ocular surface staining was significantly increased in Group 2 when compared to all other groups (one-way ANOVA p<0.05). There was no significant difference in corneal fluoroscein staining between the control and Cyclophosphamide-treated groups. The specific cellular components relevant to the ocular phenotype in this model are under current investigation.
We describe ocular surface defects that correlate with the severity of systemic GVHD, evidenced by reduced tear fluid production and significant corneal fluorescein staining. Treatment with Cyclophosphamide reduced both systemic and ocular signs of GVHD. This potentially represents a new murine model of GVHD-induced ocular surface disease and dry eye, and will be used to study the mechanisms of disease progression and novel therapeutic approaches.
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