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Epithelial mesenchymal transition in human ocular chronic graft-versus-host disease.

ABSTRACT: Chronic graft-versus-host disease (cGVHD) of the ocular surface and lacrimal gland is a vision-threatening condition that occurs after allogeneic bone marrow transplantation. In this study, we used immunohistochemistry and electron microscopy to investigate whether epithelial mesenchymal transition (EMT) contributed to the pathogenesis of ocular cGVHD. We detected down-regulation of E-cadherin and translocation of beta-catenin from the intercellular junction to the cytoplasm and nucleus of cGVHD conjunctival basal epithelia and lacrimal gland myoepithelia. Notable findings included expression of Snail, an inducer of EMT, in the nucleus of ocular cGVHD epithelia. The fibrosis markers heat shock protein 47, alpha-smooth muscle actin, and fibroblast specific protein-1 were overexpressed in ocular cGVHD epithelia. In addition, p63, a marker of conjunctival basal epithelia, was observed in the nuclei of subconjunctival cells beneath disrupted basal lamina. Disrupted basal lamina and the presence of altered collagen bundles were observed in the cytoplasm and beneath cGVHD epithelia. In contrast, these observations were rarely observed in the normal conjunctiva and in Sjögren's syndrome lacrimal gland epithelia. These findings together indicate that ocular cGVHD epithelia gain the mesenchymal phenotype and the capacity to migrate into the subepithelial stroma. Our findings suggest that EMT may be partially responsible for the conjunctival and lacrimal gland fibrosis found in patients with cGVHD.

SUBMITTER: Ogawa Y

PROVIDER: S-EPMC2789626 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Epithelial mesenchymal transition in human ocular chronic graft-versus-host disease.

Ogawa Yoko Y Shimmura Shigeto S Kawakita Tetsuya T Yoshida Satoru S Kawakami Yutaka Y Tsubota Kazuo K

The American journal of pathology 20091105 6

Chronic graft-versus-host disease (cGVHD) of the ocular surface and lacrimal gland is a vision-threatening condition that occurs after allogeneic bone marrow transplantation. In this study, we used immunohistochemistry and electron microscopy to investigate whether epithelial mesenchymal transition (EMT) contributed to the pathogenesis of ocular cGVHD. We detected down-regulation of E-cadherin and translocation of beta-catenin from the intercellular junction to the cytoplasm and nucleus of cGVHD ...[more]

PMID: 19893038

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Project description:Ocular involvement can be quite symptomatic in patients with chronic graft-versus-host disease (GVHD). The prevalence of and risk factors for ocular GVHD and its impact on quality of life (QOL) in patients with chronic GVHD were studied in a prospective, multicenter, longitudinal, observational study. This study enrolled 342 patients with 1483 follow-up visits after allogeneic hematopoietic cell transplantation. All patients in this analysis were diagnosed with chronic GVHD requiring systemic treatment and enrolled within 3 months of chronic GVHD diagnosis. The symptom burden of ocular GVHD was based on the degree of dry eye symptoms, frequency of artificial tear usage, and impact on activities of daily living. Patients' QOL was measured by self-administered questionnaires. Variables associated with ocular GVHD at enrollment and subsequent new-onset ocular GVHD and the associations with QOL were studied. Of the 284 chronic GVHD patients, 116 (41%) had ocular GVHD within 3 months of chronic GVHD diagnosis ("early ocular GVHD"). Late ocular GVHD (new onset > 3 months after chronic GVHD diagnosis) occurred in 64 patients. Overall cumulative incidence at 2 years was 57%. Female gender (P = .005), higher acute GVHD grade (P = .04), and higher prednisone dose at study entry (P = .04) were associated with early ocular GVHD. For patients who did not have ocular GVHD within 3 months of chronic GVHD diagnosis, presence of prior grades I to IV acute GVHD (HR 1.78, P = .04) was associated with shorter time to late ocular GVHD, whereas female donor-male recipient (HR .53, P = .05) was associated with longer time to late ocular GVHD onset. Using all visit data, patients with ocular GVHD had worse QOL, as measured by Functional Assessment of Cancer Therapy Bone Marrow Transplantation (P = .002), and greater chronic GVHD symptom burden, as measured by the Lee symptom overall score excluding the eye component (P < .001), compared with patients without ocular GVHD. In conclusion, this large, multicenter, prospective study shows that ocular GVHD affects 57% of patients within 2 years of chronic GVHD diagnosis. Women, patients on higher doses of prednisone at study entry, and those with a history of acute GVHD were at higher risk for ocular GVHD. Strong evidence suggests that ocular GVHD is associated with worse overall health-related QOL.

Project description:BackgroundAfter allogeneic hematopoietic stem cell transplantation (allo-HSCT), patients are followed up by transplant clinicians. Finding an effective primary screening method that transplant clinicians or patients can master is essential in the early referral of suspected chronic ocular graft-versus-host disease (coGVHD) to an ophthalmologist. This study investigated if the ocular surface disease index (OSDI) questionnaire could be used for coGVHD primary screening.MethodsThis case-controlled, cross-sectional study enrolled 161 allo-HSCT patients. All participants completed an OSDI questionnaire and underwent a silt-lamp examination. Bulbar conjunctival injection (BCI) was assessed using torchlight, while tear volume was measured via the Schirmer test (ST). The receiver operating characteristic curve was used to evaluate the sensitivity, specificity, and cutoff values of OSDI, ST, and BCI grading. Performance comparisons of the 3 tests applied in isolation, parallel, and series were made.ResultsThere were 84 patients with and 77 patients without coGVHD. Compared to those without coGVHD, patients with coGVHD had significantly higher median values of OSDI, corneal fluorescein staining, conjunctival injection, conjunctival fibrosis, and meibum quality, but lower ST scores (All P values <0.001). The cutoff values for OSDI, ST, and BCI grade in the diagnosis of coGVHD were 19.4 points, 7 mm, and grade 0, respectively. The sensitivity and specificity of the tests based on the cutoff values were, respectively, 89.3% and 89.6% for OSDI, 91.7% and 59.7% for ST, and 78.6% and 70.1% for BCI. The area under the curve (AUC) value of OSDI was significantly higher than that of ST (0.931 vs. 0.826; P=0.010) and BCI grade (0.931 vs. 0.781; P<0.001). The AUC values of the combinations were lower than that of OSDI alone.ConclusionsThe OSDI questionnaire can be used as a simple screening test for coGVHD as demonstrated by its high sensitivity and specificity in the transplant clinic and patients' self-monitoring. An OSDI greater than 19.4 could be considered an ophthalmology referral criterion.

Dataset Information

Epithelial mesenchymal transition in human ocular chronic graft-versus-host disease.

Publications

Epithelial mesenchymal transition in human ocular chronic graft-versus-host disease.

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