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Dry eye (DED) is a prevalent disease with immune-mediated inflammation as the principal pathophysiological etiology. Olive pomace, the major by-product of the olive oil industry, is rich in high-value polyphenols. Their anti-inflammatory and immunomodulatory activities were determined on human CD4+ T cells (hTCD4+) and in a DED animal model. The viability of hTCD4+ cells isolated from peripheral blood and activated with phytohemagglutinin-M was evaluated after treatment for 48 h with an olive pomace extract (OPT3, 0.10-0.40 mg/mL) and its major compound, hydroxytyrosol (25-100 mu M). Regarding the DED animal model, 100 mu M hydroxytyrosol, 0.20 mg/mL OPT3, or vehicle (borate buffer) were topically administered to 14 days-desiccating stress-exposed (constant airflow/scopolamine administration) C57BL/6 mice. Tear volume, corneal fluorescein staining (CFS), CD4+, and CD8+ T cell count in lymph nodes (flow cytometry), and IP-10 and TNF-alpha gene expression (qRT-PCR) in the cornea, conjunctiva, and lacrimal glands were evaluated. OPT3 (0.2-0.4 mg/mL) and hydroxytyrosol (100 mu M) significantly reduced hTCD4+ proliferation. In mice, both treatments reduced lacrimal gland IP-10 gene expression. OPT3 also decreased CFS, and conjunctival IP-10 and corneal TNF-alpha gene expression. In lymph nodes, hydroxytyrosol reduced CD3+, OPT3, and CD8+ count. Thus, a high-value application as a promising DED protection was proposed for olive pomace.

Purpose: Dry eye disease (DED) is a multifactorial disease, with limitations regarding efficacy and tolerability of applied substances. Among several candidates, the endocannabinoid system with its receptors (CB1R and CB2R) were reported to modulate inflammation, wound healing and pain, which are also core DED pathomechanisms. This study is to investigate the therapeutic responses of Delta-9 tetrahydrocannabinol (a non-selective agonist) and two selective antagonists, SR141716A (CB1R antagonist) and SR144528 (CB2R antagonist), as a topical application using a DED mouse model. Method: Experimental DED was induced in naive C57BL/6 mice. Expression of CBR at the ocular surface of naive and DED mice was determined by qPCR and in-situ hybridization. Either THC or CBR antagonists were compounded in an aqueous solution and dosed during the induction of DED. Tear production, cornea sensitivity, and cornea fluorescence staining were tested. At the end of each experiment, corneas were stained with beta 3-tubulin for analysis of corneal nerve morphology. Conjunctiva was analyzed for CD4(+) and CD8(+) infiltration. Results: CB1R and CB2R are present at the ocular surface, and desiccating stress increased CBR expressions (p < 0.05). After 10 days of DED induction, treated groups demonstrated a reduced CBR expression in the cornea, which was concurrent with improvements in the DED phenotype including fluorescence staining & inflammation. Applying THC protected corneal nerve morphology, thus maintained corneal sensitivity and reduced CD4(+) T-cell infiltration. The CB1R antagonist maintained cornea sensitivity without changing nerve morphology. Conclusions: Endocannabinoid receptor modulation presents a potential multi-functional therapeutic approach for DED.

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.

Despite decades of experience with hematopoietic stem cell transplantation, we are still faced with the delicate equipoise of achieving stable ocular health post-transplantation. This is because ocular graft-versus-host disease (oGvHD) following hematopoietic stem cell transplantation frequently occurs (>= 50%) among transplant patients. To date, our understanding of the pathophysiology of oGvHD especially the involvement of the meibomian gland is still limited as a result of a lack of suitable preclinical models among other. Herein, the current state of the etiology and, pathophysiology of oGvHD based on existing pre-clinical models are reviewed. The need for additional pre-clinical models and knowledge about the involvement of the meibomian glands in oGvHD are emphasized.

Introduction: Anti-inflammatory, topical therapy of severe keratitis in dry eye disease (DED) and ocular graft-versus-host disease (oGvHD) includes steroids, cyclosporine (Cs), and others. In Germany, a commercial product containing 0.1% Cs in a cationic formulation is available since 2015. Objective: The aim of this study was to present real-life data using cationic 0.1% Cs in oGvHD patients. Methods: This was a retrospective study of 26 oGvHD and 41 DED patients with corneal staining of at least Oxford grade III. Parameters analyzed were Ocular Surface Disease Index, corneal staining, intraocular pressure, tear film break-up time, Schirmer, and visual acuity. In addition, it was evaluated how different Cs formulations were tolerated. Results: Corneal staining improved significantly in 1 eye in DED but not in oGvHD. In DED, cationic 0.1% Cs was not tolerated by 32% of the patients, in contrast to 0.05% Cs in castor oil not tolerated by 47% and liposomal 0.05% Cs by 63%. In oGvHD patients, cationic 0.1% Cs was not tolerated by 62%, 0.05% Cs in castor oil by 33%, and liposomal 0.05% Cs by 39% of the patients. Conclusions: This study demonstrates differences between the tolerance of different Cs formulations depending on the underlying cause of severe keratitis. Cationic 0.1% Cs is considerably less tolerated in oGvHD, and its use should be considered with care.

Purpose: Ocular graft-versus-host disease (oGvHD) following allogeneic hematopoietic stem cell transplantation develops as severe dry eye disease (DED) and is initially treated with lubricants, although no clinical trials are available using artificial tears in oGvHD. This trial was set up to test perfluorohexyloctane (NovaTears (R)) as nonpreserved layer-forming agent for the treatment of DED in oGvHD. Methods: 25 patients with severe DED due to oGvHD received 1 drop perfluorohexyloctane 4 times daily during a prospective, multicenter, observational 12-week study on top of established topical therapy. Clinical parameters included Schirmer test, tear film breakup time, corneal staining, meibum secretion and ocular surface disease index. Adverse events, visual acuity and intraocular pressure were key safety parameters. Results: From 25 patients recruited, 23 presented for the second visit. Perfluorohexyloctane treatment did not lead to any changes in clinical or safety parameters but led to fast relief in symptoms in 57% of the patients. One adverse reaction occurred. Conclusions: This study showed no change in clinical signs in severe DED due to oGvHD, which was not unexpected due to the underlying pathomechanisms. However, the study showed improvement of symptoms in individual patients allowing application of perfluorohexyloctane as an additional symptomatic therapy in oGvHD. (C) 2019 S. Karger AG, Basel.

Conjunctiva-associated tissue (CALT) is assumed to play a crucial role in the immune system of the ocular surface. Its function in several ocular surface diseases (OSD) is still not fully understood. This study investigates the function of CALT in mouse models of dry-eye disease and ocular allergy. Since antigen-presentation is the central similarity in the pathologies, this study focuses on antigen-presentation in CALT Morphology and the expression of CALT, which was investigated in mice after induction of dry-eye, ocular allergy, topical antigen-stimulation, and after local depletion of phagocytic cells. Antigen uptake was investigated after the application of fluorescent ovalbumin (OVA). OSD influences the appearance and morphology of CALT in a disease-dependent manner. Ocular allergy leads to an increase and dry-eye disease to a decrease in number and size of CALT. The development of CALT is dependent on the presence of APCs. Professional APCs are present in CALT, and soluble antigen is transported into the follicle. CALT appearance is disease-specific and indicative of differing functions. Although the specific involvement of CALT in OSD needs further study, the existence of functional APCS and antigen-uptake supports the hypothesis that CALT is an immunological key player at the ocular surface.

Background graft-versus-host disease (GvHD) is a common complication after allogeneic haematopoietic stem cell transplantation (allo-SCT) and causes immunological rejection of host tissues, which can occur both acute or chronically. Approximately 40-80% of patients with the diagnosis of chronic GvHD (cGvHD) also develop ocular GvHD. For these patients, immediate and uncomplicated access to interdisciplinary patient-centred care is important. We performed this survey to improve understanding of the structure of patient-centred care in Germany. Methods The GvHD working party of the Cornea Section of the German Society of Ophthalmology sent the Survey of ocular GvHD 2016 to all university and specialised hospitals in Germany. We evaluated the data and compared the information with survey results from 2014, in order to draw conclusions about the structure and process of patient-centred care in ocular GvHD. Besides the questions from 2014 on the numbers of allo-SCT, frequency of examinations, etc. there were additional questions on the prescription of ciclosporin and autologous serum eye drops. The question on frequency examination was further expanded to include examinations of paediatric patients. Results Of 30 participating hospitals, 22 had already taken part in the first survey. According to the information they provided, approx. 1860 allo-SCTs were performed in the transplantation units of the participating eye hospitals in 2016. This was more than half of the transplantations performed in Germany. Ophthalmologists examined between 2 and 250 Patients per year per centre. Eight clinics provide a specialised outpatient clinic for ocular GvHD. Nearly all the participating clinics prescribe ciclosporin eye drops. About 2/3 provide autologous serum eye drops, seven obtain them from external sources. Overall approx. 125- 140 children were examined in 2016. Conclusions Due to the potential severity of ocular GvHD with immobilisation of the patients and the imminent loss o

Background: Dyslipidemia may be linked to meibomian gland dysfunction (MGD) and altered meibum lipid composition. The purpose was to determine if plasma and meibum cholesteryl esters (CE), triglycerides (TG), ceramides (Cer) and sphingomyelins (SM) change in a mouse model of diet-induced obesity where mice develop dyslipidemia. Methods: Male C57/BL6 mice (8/group, age = 6 wks) were fed a normal (ND; 15% kcal fat) or an obesogenic high-fat diet (HFD; 42% kcal fat) for 10 wks. Tear production was measured and meibography was performed. Body and epididymal adipose tissue (eAT) weights were determined. Nano-ESI-MS/MS and LC-ESI-MS/MS were used to detect CE, TG, Cer and SM species. Data were analyzed by principal component analysis, Pearson's correlation and unpaired t-tests adjusted for multiple comparisons; significance set at p <= 0.05. Results: Compared to ND mice, HFD mice gained more weight and showed heavier eAT and dyslipidemia with higher levels of plasma CE, TG, Cer and SM. HFD mice had hypertrophic meibomian glands, increased levels of lipid species acylated by saturated fatty acids in plasma and meibum and excessive tear production. Conclusions: The majority of meibum lipid species with saturated fatty acids increased with HFD feeding with evidence of meibomian gland hypertrophy and excessive tearing. The dyslipidemia is associated with altered meibum composition, a key feature of MGD.