Ocular Graft-versus-Host Disease in a Chemotherapy-Based Minor-Mismatch Mouse Model Features Corneal (Lymph-) Angiogenesis

Abstract

Ocular graft-versus-host disease (oGVHD) is a fast progressing, autoimmunological disease following hematopoietic stem cell transplantation, leading to severe inflammation of the eye and destruction of the lacrimal functional unit with consecutive sight-threatening consequences. The therapeutic “window of opportunity” is narrow, and current treatment options are limited and often insufficient. To achieve new insights into the pathogenesis and to develop new therapeutic approaches, clinically relevant models of oGVHD are desirable. In this study, the ocular phenotype was described in a murine, chemotherapy-based, minor-mismatch GVHD model mimicking early-onset chronic oGVHD, with corneal epitheliopathy, inflammation of the lacrimal glands, and blepharitis. Additionally, corneal lymphangiogenesis was observed as part of oGVHD pathogenesis for the first time, thus opening up the investigation of lymphangiogenesis as a potential therapeutic and diagnostic tool.

Olive Pomace Phenolic Compounds: From an Agro-Industrial By-Product to a Promising Ocular Surface Protection for Dry Eye Disease

“…Lymph nodes of all mice in each of the 3 groups (vehicle, HT, and OPT3-treated) were removed from all animals on the last day and mashed the same day through a cell strainer, as previously described [ 55 ]. Briefly, single-cell suspensions were transferred to FACS buffer (0.5% N,O-bis (trimethylsilyl)acetamide—BSA, 1% FBS, and Ethylenediaminetetraacetic acid—EDTA 1:50 in DPBS—Thermo Fisher Scientific, Rockford, IL, USA).…”

“…Ιnterferon γ-induced protein (IP)-10 (also known as CXCL10) and tumor necrosis factor (TNF)-α gene expression in the cornea, conjunctiva, and lacrimal gland tissues was studied by quantitative real-time polymerase chain reaction with retrotranscription (qRT-PCR). All procedures were performed as previously described [ 55 ]. The corneas and conjunctivas of two eyes per mouse were pooled in the same Eppendorf tube, while for lacrimal glands one sample per mouse was used.…”

Lymphatic vessel: Origin, heterogeneity, biological functions and therapeutic targets

“… 295 Gehlsen et al found that lymphangiogenesis is involved in the pathogenesis of ocular GVHD. 296 In addition, Mertlitz et al found that acute GVHD was associated with lymphangiogenesis in murine allo-HSCT models and in intestinal tissue biopsy samples taken from patients, while the administration of anti-VEGFR3 antibodies suppressing lymphangiogenesis ameliorated GVHD and prolonged the survival in murine models. 297 …”

Insulin eye drops for severe refractory chronic ocular graft-versus-host disease

“…It is not involved in corneal glucose uptake which is facilitated by glucose transporter-1 (GLUT1) [ 9 ]. Experimental studies, using mouse models of oGVHD [ 10 ] are under way to investigate insulin levels in tear film and its cellular effects in different phases and severities of oGVHD and to study the mode-of-action that we see in the first clinical applications.…”