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Lent-Schochet D, Akbar M, Hou JH, Farooq AV. Diagnostic approach to limbal stem cell deficiency. FRONTIERS IN OPHTHALMOLOGY 2025; 4:1524595. [PMID: 39886446 PMCID: PMC11779701 DOI: 10.3389/fopht.2024.1524595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Accepted: 12/24/2024] [Indexed: 02/01/2025]
Abstract
Limbal stem cell deficiency (LSCD) is an important cause of visual and ocular morbidity. Effective diagnosis and management require a thoughtful and comprehensive evaluation of the ocular surface. This review describes the pathogenesis, diagnosis, and grading of LSCD, as well as characteristic findings via slit lamp examination, in-vivo confocal microscopy, anterior segment optical coherence tomography (AS-OCT), impression cytology, and OCT angiography.
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Affiliation(s)
- Daniella Lent-Schochet
- Department of Ophthalmology and Visual Science, University of Chicago, Chicago, IL, United States
| | - Mizna Akbar
- Department of Ophthalmology and Visual Science, University of Chicago, Chicago, IL, United States
| | - Joshua H. Hou
- Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minnesota, MN, United States
| | - Asim V. Farooq
- Department of Ophthalmology and Visual Science, University of Chicago, Chicago, IL, United States
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2
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Surico PL, Luo ZK. Understanding Ocular Graft-versus-Host Disease to Facilitate an Integrated Multidisciplinary Approach. Transplant Cell Ther 2024; 30:S570-S584. [PMID: 38986740 DOI: 10.1016/j.jtct.2024.06.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 06/10/2024] [Accepted: 06/30/2024] [Indexed: 07/12/2024]
Abstract
Ocular graft-versus-host disease (oGVHD) remains a challenging and potentially devastating complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although oGVHD significantly impacts the quality of life of affected survivors, it often goes unrecognized, particularly in the early stages. Targeting all providers in the HSCT community who see patients regularly and frequently for their post-allo-HSCT care, this review and opinion piece introduces the basic concepts of ocular surface pathophysiology, dissects the different stages of clinical presentation of oGVHD, explains why the current diagnostic criteria tend to capture the late disease stages, and highlights the warning signs of early disease development to facilitate prompt referral of oGVHD suspects for ocular specialist care. Along with introducing a comprehensive list of treatment options, this review emphasizes basic therapeutic strategy and options that can be safely and effectively initiated by any care provider. We believe in empowering patients as well as care providers beyond disciplinary boundaries to provide the most cohesive and integrated care in a multidisciplinary approach.
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Affiliation(s)
- Pier Luigi Surico
- Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts; Department of Ophthalmology, Campus Bio-Medico University, Rome, Italy
| | - Zhonghui K Luo
- Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts.
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3
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Singh RB, Cho W, Liu C, Naderi A, Surico PL, Kahale F, Dohlman TH, Chauhan SK, Dana R. Immunopathological mechanisms and clinical manifestations of ocular graft-versus-host disease following hematopoietic stem cell transplantation. Bone Marrow Transplant 2024; 59:1049-1056. [PMID: 38822141 DOI: 10.1038/s41409-024-02321-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Revised: 05/21/2024] [Accepted: 05/23/2024] [Indexed: 06/02/2024]
Abstract
Graft-versus-host disease is among the most common clinical complications following allogeneic hematopoietic stem cell transplantation. It causes inflammation-mediated destruction and dysfunction of various organ systems including ocular tissues in 60-90% of the patients and is termed ocular GVHD (oGVHD). In oGVHD, donor-derived T-cells recognize host antigens as foreign, resulting in immune dysregulation, inflammation and fibrosis of lacrimal glands, meibomian glands, cornea, and conjunctiva. The clinical presentation in oGVHD patients range from mild dry eye symptoms to catastrophic inflammation mediated pathological changes which can cause corneal perforation and blindness. In this review article, we provide detailed insights into the impact of mucosal barrier disruption, the afferent and efferent phases of immunological response involving activation of antigen presenting cells and T cells, respectively. We evaluate the evidence outlining the effector phase of the disease leading to cellular destruction and eventually fibrosis in patients with oGVHD. Finally, we discuss the well-established criteria for the diagnosis of oGVHD.
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Affiliation(s)
- Rohan Bir Singh
- Laboratory of Ocular Immunology, Transplantation and Regeneration, Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Wonkyung Cho
- Laboratory of Ocular Immunology, Transplantation and Regeneration, Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Catherine Liu
- Laboratory of Ocular Immunology, Transplantation and Regeneration, Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Amirreza Naderi
- Laboratory of Ocular Immunology, Transplantation and Regeneration, Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Pier Luigi Surico
- Laboratory of Ocular Immunology, Transplantation and Regeneration, Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Francesca Kahale
- Laboratory of Ocular Immunology, Transplantation and Regeneration, Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Thomas H Dohlman
- Laboratory of Ocular Immunology, Transplantation and Regeneration, Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Sunil K Chauhan
- Laboratory of Ocular Immunology, Transplantation and Regeneration, Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Reza Dana
- Laboratory of Ocular Immunology, Transplantation and Regeneration, Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
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4
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Long Q, Huang C, Zhang L, Jiang H, Zhao S, Zhang L, Zheng X, Ou S, Gu H. A novel tissue-engineered corneal epithelium based on ultra-thin amniotic membrane and mesenchymal stem cells. Sci Rep 2024; 14:17407. [PMID: 39075142 PMCID: PMC11286932 DOI: 10.1038/s41598-024-68219-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 07/22/2024] [Indexed: 07/31/2024] Open
Abstract
Currently, in vitro cultured corneal epithelial transplantation is effective in treating limbal stem cell dysfunction (LSCD). Selecting carriers is crucial for constructing the corneal epithelium through tissue engineering. In this study, the traditional amniotic membrane (AM) was modified, and mesenchymal stem cells (MSCs) were inoculated into the ultra-thin amniotic membrane (UAM) stroma to construct a novel UAM-MSC tissue-engineered corneal epithelial carrier, that could effectively simulate the limbal stem cells (LSCs) microenvironment. The structure of different carriers cultured tissue-engineered corneal epithelium and the managed rabbit LSCD model corneas were observed through hematoxylin-eosin staining. Cell phenotypes were evaluated through fluorescence staining, Western blotting, and RT-qPCR. Additionally, cell junction genes and expression markers related to anti-neovascularization were evaluated using RT-qPCR. Corneal epithelium cell junctions were observed via an electron microscope. The tissue-engineered corneal epithelium culture medium was analyzed through mass spectrometry. Tissue-engineered corneal epithelial cells expanded by LSCs on UAM-MSCs had good transparency. Simultaneously, progenitor cell (K14, PNCA, p63) and corneal epithelial (PAX6) gene expression in tissue-engineered corneal epithelium constructed using UAM-MSCs was higher than that in corneal epithelial cells amplified by UAM and de-epithelialized amniotic membrane. Electron microscopy revealed that corneal epithelial cells grafted with UAM-MSCs were closely connected. In conclusion, the UAM-MSCs vector we constructed could better simulate the limbal microenvironment; the cultured tissue-engineered corneal epithelium had better transparency, anti-neovascularization properties, closer intercellular connections, and closer resemblance to the natural corneal epithelial tissue phenotype.
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Affiliation(s)
- Qiurong Long
- Guizhou Medical University, Guiyang, Guizhou, China
- The Affiliated Hospital of Guizhou Medical University, No.9 Beijing Road, Yunyan District, Guiyang, Guizhou, China
| | - Chao Huang
- Guizhou Medical University, Guiyang, Guizhou, China
| | - Liying Zhang
- Guizhou Medical University, Guiyang, Guizhou, China
- The Affiliated Hospital of Guizhou Medical University, No.9 Beijing Road, Yunyan District, Guiyang, Guizhou, China
| | - Hao Jiang
- Guizhou Medical University, Guiyang, Guizhou, China
- The Affiliated Hospital of Guizhou Medical University, No.9 Beijing Road, Yunyan District, Guiyang, Guizhou, China
| | - Su Zhao
- Guizhou Medical University, Guiyang, Guizhou, China
- The Affiliated Hospital of Guizhou Medical University, No.9 Beijing Road, Yunyan District, Guiyang, Guizhou, China
| | - Lingli Zhang
- Guizhou Medical University, Guiyang, Guizhou, China
| | - Xueer Zheng
- Guizhou Medical University, Guiyang, Guizhou, China
| | - Shangkun Ou
- Guizhou Medical University, Guiyang, Guizhou, China.
- The Affiliated Hospital of Guizhou Medical University, No.9 Beijing Road, Yunyan District, Guiyang, Guizhou, China.
| | - Hao Gu
- Guizhou Medical University, Guiyang, Guizhou, China.
- The Affiliated Hospital of Guizhou Medical University, No.9 Beijing Road, Yunyan District, Guiyang, Guizhou, China.
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Stern ME, Theofilopoulos AN, Steven P, Niederkorn JY, Fox R, Calonge M, Scheid C, Pflugfelder SC. Immunologic basis for development of keratoconjunctivitis sicca in systemic autoimmune diseases: Role of innate immune sensors. Ocul Surf 2024; 32:130-138. [PMID: 38395195 DOI: 10.1016/j.jtos.2024.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 02/12/2024] [Accepted: 02/18/2024] [Indexed: 02/25/2024]
Abstract
The literature is filled with citations reporting an increased incidence of chronic dry eye disease, also known as keratoconjunctivitis sicca, in patients with systemic autoimmune diseases such as rheumatoid arthritis, Sjögren's Syndrome, systemic sclerosis and lupus. As the most environmentally exposed mucosal surface of the body, the conjunctiva constantly responds to environmental challenges which are typically self limited, but when persistent and unresolved may provoke pathogenic innate and adaptive immune reactions. Our understanding of the pathophysiological mechanisms by which systemic autoimmune diseases cause dry eye inducing ocular surface inflammation continues to evolve. Conjunctival immune tone responds to self or foreign danger signals (including desiccating stress) on the ocular surface with an initial non-specific innate inflammatory response. If unchecked, this can lead to activation of dendritic cells that present antigen and prime T and B cells resulting in an adaptive immune reaction. These reactions generally resolve, but dysfunctional, hyper-responsive immune cells found in systemic autoimmune diseases that are recruited to the ocular surface can amplify inflammatory stress responses in the ocular surface and glandular tissues and result in autoimmune reactions that disrupt tear stability and lead to chronic dry eye disease. We here propose that unique features of the ocular surface immune system and the impact of systemic immune dysregulation in autoimmune diseases, can predispose to development of dry eye disease, and exacerbate severity of existing dry eye.
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Affiliation(s)
- Michael E Stern
- University of Cologne, Department of Ophthalmology, Cologne, Germany; IOBA, Department of Ophthalmology, University of Valladolid, Valladolid, Spain.
| | | | - Philipp Steven
- University of Cologne, Department of Ophthalmology, Cologne, Germany; University of Cologne, Department of Internal Medicine - 1, Cologne, Germany
| | - Jerry Y Niederkorn
- Southwestern School of Medicine, Department of Ophthalmology, Dallas, TX, USA
| | - Robert Fox
- Scripps Hospital, Department of Rheumatology, La Jolla, CA, USA
| | - Margarita Calonge
- IOBA, Department of Ophthalmology, University of Valladolid, Valladolid, Spain
| | - Christof Scheid
- University of Cologne, Department of Internal Medicine - 1, Cologne, Germany
| | - Stephen C Pflugfelder
- Ocular Surface Center, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA
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Rossi C, Buizza A, Alessio G, Borselli M, Taloni A, Carnevali A, Carnovale Scalzo G, Lucisano A, Scorcia V, Giannaccare G. Ophthalmic Manifestations in Patients with Blood Malignancies. Hematol Rep 2024; 16:193-203. [PMID: 38651449 PMCID: PMC11036248 DOI: 10.3390/hematolrep16020020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Revised: 03/13/2024] [Accepted: 03/26/2024] [Indexed: 04/25/2024] Open
Abstract
Ocular complications can occur in up to 90% of patients with blood malignancies. Such complications range from direct infiltration to local hemostatic imbalance and treatment-related toxicity. This narrative review is based on a systematic computerized search of the literature conducted until January 2024 and examines the common ocular complications associated with blood cancers. Ocular complications from primary disease include mass effects from ocular adnexal lymphomas and intraocular lymphomas, with B-cell lymphomas accounting for 95% of primary ocular presentations. Secondary disease involvement from systemic hematological malignancies can lead to a wide range of ocular manifestations, such as leukemic retinopathy. Furthermore, toxicity from antineoplastic therapies and ocular graft versus host disease (oGVHD) after hematopoietic stem cell transplantation present additional risks to ocular health. In conclusion, ocular complications in blood cancer patients are an integral part of patient management, requiring regular ophthalmic evaluations and close collaboration between oncologists and ophthalmologists. Advances in therapy and an increased focus on early symptom recognition are essential for preserving vision and enhancing patient quality of life.
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Affiliation(s)
- Costanza Rossi
- Department of Ophthalmology, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy; (C.R.); (G.A.); (M.B.); (A.T.); (A.C.); (G.C.S.); (A.L.); (V.S.)
| | - Alessandro Buizza
- Department of Biomedical Sciences, Humanitas University, via Rita Levi Montalcini 4, 20072 Milan, Italy;
- IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Milan, Italy
| | - Giuseppe Alessio
- Department of Ophthalmology, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy; (C.R.); (G.A.); (M.B.); (A.T.); (A.C.); (G.C.S.); (A.L.); (V.S.)
| | - Massimiliano Borselli
- Department of Ophthalmology, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy; (C.R.); (G.A.); (M.B.); (A.T.); (A.C.); (G.C.S.); (A.L.); (V.S.)
| | - Andrea Taloni
- Department of Ophthalmology, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy; (C.R.); (G.A.); (M.B.); (A.T.); (A.C.); (G.C.S.); (A.L.); (V.S.)
| | - Adriano Carnevali
- Department of Ophthalmology, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy; (C.R.); (G.A.); (M.B.); (A.T.); (A.C.); (G.C.S.); (A.L.); (V.S.)
| | - Giovanna Carnovale Scalzo
- Department of Ophthalmology, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy; (C.R.); (G.A.); (M.B.); (A.T.); (A.C.); (G.C.S.); (A.L.); (V.S.)
| | - Andrea Lucisano
- Department of Ophthalmology, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy; (C.R.); (G.A.); (M.B.); (A.T.); (A.C.); (G.C.S.); (A.L.); (V.S.)
| | - Vincenzo Scorcia
- Department of Ophthalmology, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy; (C.R.); (G.A.); (M.B.); (A.T.); (A.C.); (G.C.S.); (A.L.); (V.S.)
| | - Giuseppe Giannaccare
- Eye Clinic, Department of Surgical Sciences, University of Cagliari, 09123 Cagliari, Italy
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7
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Chiang TL, Sun YC, Wu JH, Hsieh YT, Huang WL, Chen WL. The ocular graft-versus-host disease: the path from current knowledge to future managements. Eye (Lond) 2023; 37:1982-1992. [PMID: 36333534 PMCID: PMC10333261 DOI: 10.1038/s41433-022-02288-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 08/26/2022] [Accepted: 10/07/2022] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND Graft-versus-host disease (GVHD) is one of the major complications of allogenic haematopoietic stem cell transplantation (HSCT). The manifestation of ocular GVHD (oGVHD) is variable and may involve cornea, lacrimal gland, conjunctiva, eyelid, and/or nasolacrimal duct. We reviewed and summarized the current managements of oGVHD with specific focus on the emerging therapeutic advances. METHODS PubMed, Web of Science, and Google Scholar were searched for relevant literatures published within 20 years. Keywords used included "Graft-Versus-Host Disease", "GVHD", "ocular", "ocular surface", "ocular GVHD", "oGVHD", "dry eye", "keratitis", etc. RESULTS: Current managements of oGVHD can be classified into topical immunosuppressants, local tear-preservatory treatments, local non-pharmacological/surgical interventions, and systemic treatments. Additionally, some innovative therapies with promising treatment effects have been proposed, including topical target therapies, epitheliotrophic and neurotrophic treatments, recombinant DNase eye drops, mesenchymal stromal cell injection, and more. CONCLUSIONS Clinical managements of oGVHD are administered in a symptom-based, stepwise manner. The advances in innovative therapies may help improve clinical outcomes, and it is essential that physicians stay updated with these novel treatment options.
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Affiliation(s)
- Tung-Lin Chiang
- School of Medicine, National Taiwan University, Taipei, Taiwan
| | - Yi-Chen Sun
- Department of Ophthalmology, Taipei Tzu Chi Hospital, The Buddhist Tzu Chi Medical Foundation, Taipei, Taiwan
- College of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Jo-Hsuan Wu
- Shiley Eye Institute and Viterbi Family Department of Ophthalmology, University of California, San Diego, La Jolla, CA, USA
| | - Ying-Tung Hsieh
- School of Medicine, National Taiwan University, Taipei, Taiwan
| | - Wei-Lun Huang
- Department of Ophthalmology, National Taiwan University Hospital Hsinchu Branch, Hsinchu, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Wei-Li Chen
- Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan.
- Advanced Ocular Surface and Corneal Nerve Regeneration Centre, National Taiwan University Hospital, Taipei, Taiwan.
- Department of Ophthalmology, College of Medicine, National Taiwan University, Taipei, Taiwan.
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Lee DH, Margolis MS, Iovieno A, Ling J, Ng T, Djalilian AR, Yeung SN. Superior limbic keratoconjunctivitis: Update on pathophysiology and management. Ocul Surf 2023; 28:144-152. [PMID: 37011726 DOI: 10.1016/j.jtos.2023.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 03/17/2023] [Accepted: 03/31/2023] [Indexed: 04/03/2023]
Abstract
Superior limbic keratoconjunctivitis (SLK) is an under-recognized condition characterized by a final common pathologic presentation of superior conjunctival and limbal inflammation and staining. Existing literature attributes both microtrauma and local inflammation, frequently in the setting of tear film insufficiency, as the underlying mechanisms that lead to a self-perpetuating pathologic process dependent in on inflammatory cells and signaling. Effective treatments act by targeting inflammation and by mitigating mechanical stressors. This critical review discusses the latest in our understanding of the pathophysiology of SLK and how it guides our treatment strategies.
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Affiliation(s)
- Dong-Ho Lee
- Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, BC, CanadaA.
| | - Mathew S Margolis
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, University of Illinois Chicago, Chicago, IL, USA
| | - Alfonso Iovieno
- Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, BC, CanadaA
| | - Jennifer Ling
- Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, BC, CanadaA
| | - Tony Ng
- Department Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Ali R Djalilian
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, University of Illinois Chicago, Chicago, IL, USA
| | - Sonia N Yeung
- Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, BC, CanadaA
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Liao Y, Zhao W, Yang J, Wu S, Jin L, Huang F, Liang L. Vision-specific and cancer-specific quality of life in ocular graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Graefes Arch Clin Exp Ophthalmol 2023; 261:453-465. [PMID: 36029303 DOI: 10.1007/s00417-022-05812-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 07/20/2022] [Accepted: 08/16/2022] [Indexed: 01/17/2023] Open
Abstract
PURPOSE To compare the vision-specific and cancer-specific quality of life (QOL) between patients with and without ocular graft-versus-host disease (oGVHD) after allogeneic hematopoietic stem cell transplantation (alloHCT). METHODS This cross-sectional observational study analyzed 142 patients after alloHCT including 94 patients with oGVHD and 48 without. oGVHD was diagnosed according to International Chronic Ocular GVHD Consensus Group (ICOGCG) criteria. QOL was assessed by using the 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). RESULTS Compared with non-oGVHD patients, patients with oGVHD had worse vision-specific (NEI VFQ-25: 64.3 ± 20.3 vs. 77.6 ± 19.3, P < 0.001) and cancer-specific (EORTC QLQ-C30: 59.9 ± 20.3 vs. 67.4 ± 17.5, P = 0.03) QOL, as well as impaired cognitive function (72.7 ± 22.1 vs. 82.3 ± 19.0, P = 0.01). The vision-specific QOL was significantly correlated with ICOGCG score (β = - 1.88, 95%CI: - 3.35 to - 0.41, P = 0.01) and post-alloHCT medical expense (β = - 5.70, 95%CI: - 10.35 to - 1.05, P = 0.02), while cancer-specific QOL was strikingly correlated with post-alloHCT medical expense (β = - 9.91, 95%CI: - 14.43 to - 5.39, P < 0.001), frequency of ophthalmic medication (β = - 0.93, 95%CI: - 1.64 to - 0.21, P = 0.01), education (β = - 6.97, 95%CI: - 13.31 to - 0.62, P = 0.03), and peripheral blood stem cell use (β = - 6.42, 95%CI: - 12.59 to - 0.25, P = 0.04). CONCLUSIONS Patients with oGVHD experienced significant impairment in both vision-specific and cancer-specific QOL including cognitive function when compared with those without after alloHCT. Multidimensional QOL assessment should be included in the long-term alloHCT survivorship care.
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Affiliation(s)
- Yinglin Liao
- State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Disease, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, 510060, China
| | - Wenxin Zhao
- State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Disease, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, 510060, China
| | - Jing Yang
- State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Disease, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, 510060, China
| | - Shaowen Wu
- State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Disease, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, 510060, China
| | - Ling Jin
- State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Disease, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, 510060, China
| | - Fen Huang
- Department of Hematology, Nanfang Hospital, Southern Medical University, 1838S North of Guangzhou Avenue, Guangzhou, 510515, China.
| | - Lingyi Liang
- State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Disease, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, 510060, China.
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10
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Cheng X, Huang R, Huang S, Fan W, Yuan R, Wang X, Zhang X. Recent advances in ocular graft-versus-host disease. Front Immunol 2023; 14:1092108. [PMID: 36761771 PMCID: PMC9905686 DOI: 10.3389/fimmu.2023.1092108] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 01/10/2023] [Indexed: 01/26/2023] Open
Abstract
Ocular graft-versus-host-disease (GVHD) remains a significant clinical complication after allogeneic hematopoietic stem cell transplantation. Impaired visual function, pain, and other symptoms severely affect affected individuals' quality of life. However, the diagnosis of and therapy for ocular GVHD involve a multidisciplinary approach and remain challenging for both hematologists and ophthalmologists, as there are no unified international criteria. Through an exploration of the complex pathogenesis of ocular GVHD, this review comprehensively summarizes the pathogenic mechanism, related tear biomarkers, and clinical characteristics of this disease. Novel therapies based on the mechanisms are also discussed to provide insights into the ocular GVHD treatment.
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Affiliation(s)
- Xianjing Cheng
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, China.,School of Medicine, Chongqing University, Chongqing, China
| | - Ruihao Huang
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, China
| | - Shiqin Huang
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, China
| | - Wei Fan
- Department of Ophthalmology, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Rongdi Yuan
- Department of Ophthalmology, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Xiaoqi Wang
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, China
| | - Xi Zhang
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, China.,School of Medicine, Chongqing University, Chongqing, China.,Jinfeng Laboratory, Chongqing, China
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11
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Ying PX, Fu M, Huang C, Li ZH, Mao QY, Fu S, Jia XH, Cao YC, Hong LB, Cai LY, Guo X, Liu RB, Meng FK, Yi GG. Profile of biological characterizations and clinical application of corneal stem/progenitor cells. World J Stem Cells 2022; 14:777-797. [PMID: 36483848 PMCID: PMC9724387 DOI: 10.4252/wjsc.v14.i11.777] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Revised: 11/08/2022] [Accepted: 11/23/2022] [Indexed: 12/13/2022] Open
Abstract
Corneal stem/progenitor cells are typical adult stem/progenitor cells. The human cornea covers the front of the eyeball, which protects the eye from the outside environment while allowing vision. The location and function demand the cornea to maintain its transparency and to continuously renew its epithelial surface by replacing injured or aged cells through a rapid turnover process in which corneal stem/progenitor cells play an important role. Corneal stem/progenitor cells include mainly corneal epithelial stem cells, corneal endothelial cell progenitors and corneal stromal stem cells. Since the discovery of corneal epithelial stem cells (also known as limbal stem cells) in 1971, an increasing number of markers for corneal stem/progenitor cells have been proposed, but there is no consensus regarding the definitive markers for them. Therefore, the identification, isolation and cultivation of these cells remain challenging without a unified approach. In this review, we systematically introduce the profile of biological characterizations, such as anatomy, characteristics, isolation, cultivation and molecular markers, and clinical applications of the three categories of corneal stem/progenitor cells.
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Affiliation(s)
- Pei-Xi Ying
- Department of Ophthalmology, Zhujiang Hospital, The Second Clinical School, Southern Medical University, Guangzhou 510280, Guangdong Province, China
| | - Min Fu
- Department of Ophthalmology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, Guangdong Province, China
| | - Chang Huang
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai 200030, China
- NHC Key Laboratory of Myopia, Fudan University, Shanghai 200030, China
- Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai 200030, China
| | - Zhi-Hong Li
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Lab of Shock and Microcirculation, Nanfang Hospital, Southern Medical University, Guangzhou 510550, Guangdong Province, China
| | - Qing-Yi Mao
- The Second Clinical School, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Sheng Fu
- Hengyang Medical School, The University of South China, Hengyang 421001, Hunan Province, China
| | - Xu-Hui Jia
- The Second Clinical School, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Yu-Chen Cao
- The Second Clinical School, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Li-Bing Hong
- The Second Clinical School, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Li-Yang Cai
- The Second Clinical School, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Xi Guo
- Medical College of Rehabilitation, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Ru-Bing Liu
- The Second Clinical School, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Fan-ke Meng
- Emergency Department, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, Guangdong Province, China
| | - Guo-Guo Yi
- Department of Ophthalmology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, Guangdong Province, China
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12
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Trindade M, Rodrigues M, Pozzebon ME, Aranha FJP, Colella MP, Fernandes A, Fornazari DO, de Almeida Borges D, Vigorito AC, Alves M. A plethora of ocular surface manifestations in a multidisciplinary ocular graft-versus-host disease unit. Sci Rep 2022; 12:15926. [PMID: 36151252 PMCID: PMC9508128 DOI: 10.1038/s41598-022-19990-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Accepted: 09/07/2022] [Indexed: 11/09/2022] Open
Abstract
To describe the experience in a recently created ocular graft-versus-host disease unit in a tertiary hospital and to detail ocular surface features and complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). This retrospective study included all patients who underwent allo-HSCT, with or without chronic GVHD and were being monitored in the Hematopoietic Stem Cell Transplantation Unit in the UNICAMP Clinical Hospital (Campinas, Sao Paulo, Brazil) from 2015 to 2020. Patients were concomitantly evaluated by hematology and ophthalmology teams of the Ocular GVHD Unit. Hematologists performed a comprehensive systemic evaluation searching and grading mouth, skin, lungs, gastrointestinal tract, liver and genitalia GVHD. While ophthalmologists evaluated ocular symptoms through specific questionnaire (Ocular Surface Disease Index-OSDI) and a protocol of distinct ocular surface parameters for dry eye disease (1) and ocular complications, which encompassed meniscometry, non-invasive tear break-up time (NITBUT) measurement, conjunctival hyperemia quantification, meibography, fluorescein and lissamine staining and Schirmer's test. Patients were diagnosed with chronic GVHD using the National Institutes of Health (NIH) Consensus Criteria for Chronic Graft-versus-Host Disease. The International Chronic Ocular GVHD Consensus Group (ICOGCG) score was obtained at the onset of ocular disease presentation or afterwards. A total of 82 patients underwent allo-HSCT (97.6% full matched and 2.4% haploidentical), mainly for cases of leukemia and 73.2% had chronic GVHD. Mean onset time for chronic GVHD was 232 ± 7.75 days. The mouth, skin, and eyes were the main organs involved (63%, 50%, and 48%, respectively). Symptom scores and all ocular surface parameters differ in patients with and without chronic GVHD and along different timepoints of the follow-up. Ocular complications mostly involved were severe DED and meibomian gland dysfunction, conjunctival scarring, cataract and infections resulting in keratitis and corneal perforation. As therapeutic strategies, 73% patients received preservative-free lubricants, 27% autologous serum, 48% topical steroids, 27% oral tetracycline derivatives, 22% mucolytic eye drops and 3 patients needed bandage contact lens. Ocular GVHD is a complex and challenging disease with varied manifestations, resulting in a broad range of ocular test endpoints, and inconsistent treatment responses. The main ocular presentations were dry eye, meibomian gland dysfunction and cataracts. The therapeutic approach often involves topical steroids and autologous serum tears. It is important to monitor these patients closely, so the ocular GVHD Unit may improve the care, providing prompt identification of ocular manifestations and faster treatment of complications.
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Affiliation(s)
- Marilia Trindade
- Department of Ophthalmology, School of Medical Sciences, University of Campinas (UNICAMP), Rua Vital Brasil, Cidade Universitária, 13083-888, Campinas, SP, Brasil.
| | - Melina Rodrigues
- Department of Internal Medicine (Hematology), School of Medical Sciences, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Maria Eugenia Pozzebon
- Department of Ophthalmology, School of Medical Sciences, University of Campinas (UNICAMP), Rua Vital Brasil, Cidade Universitária, 13083-888, Campinas, SP, Brasil
| | - Francisco José Penteado Aranha
- Department of Internal Medicine (Hematology), School of Medical Sciences, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Marcos Paulo Colella
- Department of Internal Medicine (Hematology), School of Medical Sciences, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Arthur Fernandes
- Department of Biosciences, University of Calgary, Calgary, Canada
| | - Denise Oliveira Fornazari
- Department of Ophthalmology, School of Medical Sciences, University of Campinas (UNICAMP), Rua Vital Brasil, Cidade Universitária, 13083-888, Campinas, SP, Brasil
| | - Daniel de Almeida Borges
- Department of Ophthalmology, School of Medical Sciences, University of Campinas (UNICAMP), Rua Vital Brasil, Cidade Universitária, 13083-888, Campinas, SP, Brasil
| | - Afonso Celso Vigorito
- Department of Internal Medicine (Hematology), School of Medical Sciences, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Monica Alves
- Department of Ophthalmology, School of Medical Sciences, University of Campinas (UNICAMP), Rua Vital Brasil, Cidade Universitária, 13083-888, Campinas, SP, Brasil
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13
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Cheng C, Zhu M, Lin T, Chen Z, Zeng W, Li K, Xue R, Duan F, Wu K. Recharacterization of superior limbic keratoconjunctivitis via a subdividing grading method in 236 Chinese patients. Graefes Arch Clin Exp Ophthalmol 2022; 260:2291-2298. [PMID: 35113250 DOI: 10.1007/s00417-022-05575-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 01/17/2022] [Accepted: 01/21/2022] [Indexed: 11/04/2022] Open
Abstract
PURPOSE Superior limbic keratoconjunctivitis (SLK) is an uncommon and often overlooked chronic ocular surface disease. This retrospective consecutive case series study on Chinese patients aimed to characterize the features of this disease, including those undescribed in previous literature. METHODS Two hundred thirty-six patients diagnosed with SLK were enrolled into this consecutive case study from 2016 to 2019. The demographics, symptoms, Ocular Surface Disease Index, and ocular signs were collected and analyzed. A scoring system (SLK scale index, SSI) that integrated five major sign scores was applied to evaluate SLK severity. RESULTS Of the 236 SLK patients, dryness was the most common complaint (59.3%). Of 459 SLK eyes, superior limbus/conjunctival staining (SCS) was present in 98% eyes, followed by the superior tarsal conjunctival alterations (85.2%) and superior bulbar conjunctiva hyperemia (80.8%). Approximately 63% of eyes were accompanied by corneal staining. Superior bulbar conjunctivochalasis was a relatively rare sign (41.6%). Among the five major signs, only the prevalence of SCS gradually increased with its severity. In addition, fluorescein staining at the inferior limbus and adjacent conjunctiva (ICS) was found positive in 163 eyes of 84 patients (36%) who had significantly higher SSI than those without ICS (p = 0.013). CONCLUSIONS We found that SCS is the most common out of the 5 typical signs of SLK. ICS, a new sign, occurred in one-third of patients. SCS, a simple marker of SLK, as well as SSI, an integrated evaluation system, had the advantage of evaluating the severity and objectively characterizing SLK in clinical practice.
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Affiliation(s)
- Chao Cheng
- Zhongshan Ophthalmic Center, State Key Laboratory of Ophthalmology, Sun Yat-Sen University, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, 510060, People's Republic of China
| | - Minyi Zhu
- Zhongshan Ophthalmic Center, State Key Laboratory of Ophthalmology, Sun Yat-Sen University, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, 510060, People's Republic of China.,Department of Ophthalmology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, People's Republic of China
| | - Tianlan Lin
- Zhongshan Ophthalmic Center, State Key Laboratory of Ophthalmology, Sun Yat-Sen University, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, 510060, People's Republic of China
| | - Ziyan Chen
- Zhongshan Ophthalmic Center, State Key Laboratory of Ophthalmology, Sun Yat-Sen University, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, 510060, People's Republic of China
| | - Weiting Zeng
- Zhongshan Ophthalmic Center, State Key Laboratory of Ophthalmology, Sun Yat-Sen University, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, 510060, People's Republic of China
| | - Kunke Li
- Zhongshan Ophthalmic Center, State Key Laboratory of Ophthalmology, Sun Yat-Sen University, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, 510060, People's Republic of China
| | - Ran Xue
- Zhongshan Ophthalmic Center, State Key Laboratory of Ophthalmology, Sun Yat-Sen University, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, 510060, People's Republic of China
| | - Fang Duan
- Zhongshan Ophthalmic Center, State Key Laboratory of Ophthalmology, Sun Yat-Sen University, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, 510060, People's Republic of China
| | - Kaili Wu
- Zhongshan Ophthalmic Center, State Key Laboratory of Ophthalmology, Sun Yat-Sen University, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, 510060, People's Republic of China.
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14
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Wolff D, Radojcic V, Lafyatis R, Cinar R, Rosenstein RK, Cowen EW, Cheng GS, Sheshadri A, Bergeron A, Williams KM, Todd JL, Teshima T, Cuvelier GDE, Holler E, McCurdy SR, Jenq RR, Hanash AM, Jacobsohn D, Santomasso BD, Jain S, Ogawa Y, Steven P, Luo ZK, Dietrich-Ntoukas T, Saban D, Bilic E, Penack O, Griffith LM, Cowden M, Martin PJ, Greinix HT, Sarantopoulos S, Socie G, Blazar BR, Pidala J, Kitko CL, Couriel DR, Cutler C, Schultz KR, Pavletic SZ, Lee SJ, Paczesny S. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IV. The 2020 Highly morbid forms report. Transplant Cell Ther 2021; 27:817-835. [PMID: 34217703 PMCID: PMC8478861 DOI: 10.1016/j.jtct.2021.06.001] [Citation(s) in RCA: 93] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 06/01/2021] [Indexed: 12/12/2022]
Abstract
Chronic graft-versus-host disease (GVHD) can be associated with significant morbidity, in part because of nonreversible fibrosis, which impacts physical functioning (eye, skin, lung manifestations) and mortality (lung, gastrointestinal manifestations). Progress in preventing severe morbidity and mortality associated with chronic GVHD is limited by a complex and incompletely understood disease biology and a lack of prognostic biomarkers. Likewise, treatment advances for highly morbid manifestations remain hindered by the absence of effective organ-specific approaches targeting "irreversible" fibrotic sequelae and difficulties in conducting clinical trials in a heterogeneous disease with small patient numbers. The purpose of this document is to identify current gaps, to outline a roadmap of research goals for highly morbid forms of chronic GVHD including advanced skin sclerosis, fasciitis, lung, ocular and gastrointestinal involvement, and to propose strategies for effective trial design. The working group made the following recommendations: (1) Phenotype chronic GVHD clinically and biologically in future cohorts, to describe the incidence, prognostic factors, mechanisms of organ damage, and clinical evolution of highly morbid conditions including long-term effects in children; (2) Conduct longitudinal multicenter studies with common definitions and research sample collections; (3) Develop new approaches for early identification and treatment of highly morbid forms of chronic GVHD, especially biologically targeted treatments, with a special focus on fibrotic changes; and (4) Establish primary endpoints for clinical trials addressing each highly morbid manifestation in relationship to the time point of intervention (early versus late). Alternative endpoints, such as lack of progression and improvement in physical functioning or quality of life, may be suitable for clinical trials in patients with highly morbid manifestations. Finally, new approaches for objective response assessment and exploration of novel trial designs for small populations are required.
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Affiliation(s)
- Daniel Wolff
- Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany.
| | - Vedran Radojcic
- Division of Hematology and Hematologic Malignancies, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah
| | - Robert Lafyatis
- Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Resat Cinar
- Section on Fibrotic Disorders, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Rachel K Rosenstein
- Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey
| | - Edward W Cowen
- Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland
| | - Guang-Shing Cheng
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Medicine, University of Washington, Seattle, Washington
| | - Ajay Sheshadri
- Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Anne Bergeron
- Department of Pulmonary Medicine, AP-HP Saint Louis Hospital & University of Paris, Paris, France
| | - Kirsten M Williams
- Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, Georgia
| | - Jamie L Todd
- Division of Pulmonary, Allergy and Critical Care Medicine, Duke University, Durham, North Carolina
| | - Takanori Teshima
- Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan
| | - Geoffrey D E Cuvelier
- Pediatric Blood and Marrow Transplant, CancerCare Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Ernst Holler
- Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany
| | - Shannon R McCurdy
- Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Robert R Jenq
- Departments of Genomic Medicine and Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Alan M Hanash
- Departments of Medicine and Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York
| | - David Jacobsohn
- Children's National Hospital, George Washington University, Washington, District of Columbia
| | - Bianca D Santomasso
- Department of Neurology, Memorial Sloan Kettering Cancer Center, New York New York
| | - Sandeep Jain
- Department of Ophthalmology, University of Illinois Eye & Ear Infirmary, Chicago, Illinois
| | - Yoko Ogawa
- Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan
| | - Philipp Steven
- Division for Dry-Eye and ocular GvHD, Department of Ophthalmology, Medical Faculty and University Hospital, University of Cologne, Cologne, Germany
| | - Zhonghui Katie Luo
- Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts
| | - Tina Dietrich-Ntoukas
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin und Humboldt-Universität Berlin, Department of Ophthalmology, Berlin, Germany
| | - Daniel Saban
- Department of Ophthalmology and Department of Immunology, Duke University School of Medicine, Durham, North Carolina
| | - Ervina Bilic
- Department of Neurology, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Olaf Penack
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology and Tumorimmunology, Berlin, Germany
| | - Linda M Griffith
- Division of Allergy Immunology and Transplantation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
| | | | - Paul J Martin
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Medicine, University of Washington, Seattle, Washington
| | | | - Stefanie Sarantopoulos
- Division of Hematological Malignancies and Cellular Therapy, Duke University Department of Medicine, Duke Cancer Institute, Durham, North Carolina
| | - Gerard Socie
- Hematology Transplantation, AP-HP Saint Louis Hospital & University of Paris, Paris, France
| | - Bruce R Blazar
- Department of Pediatrics, Division of Blood & Marrow Transplant & Cellular Therapy, University of Minnesota, Minneapolis, Minnesota
| | - Joseph Pidala
- Department of Blood and Marrow Transplantation and Cellular Immunotherapy. H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Carrie L Kitko
- Pediatric Stem Cell Transplant Program, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Daniel R Couriel
- Division of Hematology and Hematologic Malignancies, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah
| | - Corey Cutler
- Division of Stem Cell Transplantation and Cellular Therapy, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Kirk R Schultz
- Pediatric Hematology/Oncology/BMT, BC Children's Hospital, Vancouver, British Columbia, Canada
| | - Steven Z Pavletic
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Stephanie J Lee
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Medicine, University of Washington, Seattle, Washington
| | - Sophie Paczesny
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina
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15
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Tong CM, He B, Iovieno A, Yeung SN. Diagnosis and management of limbal stem cell deficiency, challenges, and future prospects. EXPERT REVIEW OF OPHTHALMOLOGY 2021. [DOI: 10.1080/17469899.2021.1933441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Affiliation(s)
- C. Maya Tong
- Department of Ophthalmology and Visual Sciences, University of Alberta, Edmonton, Canada
| | - Bonnie He
- Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, Canada
| | - Alfonso Iovieno
- Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, Canada
| | - Sonia N. Yeung
- Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, Canada
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16
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Lahoti S, Weiss M, Johnson DA, Kheirkhah A. Superior limbic keratoconjunctivitis: a comprehensive review. Surv Ophthalmol 2021; 67:331-341. [PMID: 34077767 DOI: 10.1016/j.survophthal.2021.05.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 05/19/2021] [Accepted: 05/24/2021] [Indexed: 11/19/2022]
Abstract
Superior limbic keratoconjunctivitis (SLK) is characterized by chronic inflammation of the superior limbus and superior bulbar and tarsal conjunctivae. Patients also often have fine punctate staining of the limbus and adjacent area, superior limbic proliferation seen as thickening of the limbal epithelium and surrounding conjunctiva, and occasionally filaments at the superior limbus and upper cornea. SLK frequently presents with ocular irritation, foreign body sensation, and photophobia. SLK can be associated with other ocular and non-ocular conditions, such as thyroid disease. Although the pathogenesis of SLK is still unknown, it is thought to be related to mechanical injury, tear film instability, or an autoimmune/inflammatory etiology. Many patients with SLK can be asymptomatic or have symptoms that resolve or remit spontaneously. For symptomatic SLK, patients are managed medically with treatments such as lubricants, topical anti-inflammatory or immunomodulatory medications, punctal occlusion, and bandage contact lenses. Patients with symptoms refractory to medical management may need surgical interventions. We detail the current literature on the epidemiology, clinical manifestations, associated conditions, histopathology, pathogenesis, and treatment of SLK.
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Affiliation(s)
- Sejal Lahoti
- Department of Ophthalmology, University of Texas Health San Antonio, San Antonio, TX, USA
| | - Menachem Weiss
- Department of Ophthalmology, University of Texas Health San Antonio, San Antonio, TX, USA
| | - Daniel A Johnson
- Department of Ophthalmology, University of Texas Health San Antonio, San Antonio, TX, USA
| | - Ahmad Kheirkhah
- Department of Ophthalmology, University of Texas Health San Antonio, San Antonio, TX, USA.
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17
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Nair S, Vanathi M, Mukhija R, Tandon R, Jain S, Ogawa Y. Update on ocular graft-versus-host disease. Indian J Ophthalmol 2021; 69:1038-1050. [PMID: 33913829 PMCID: PMC8186644 DOI: 10.4103/ijo.ijo_2016_20] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Ocular graft-versus-host disease (oGVHD) occurs as a complication following hematopoietic stem cell transplantation and is associated with significant ocular morbidity resulting in a marked reduction in the quality of life. With no current consensus on treatment protocols, management becomes challenging as recurrent oGVHD often refractory to conventional treatment. Most authors now diagnose and grade the disease based on criteria provided by the National Institutes of Health Consensus Conference (NIH CC) or the International Chronic oGVHD (ICCGVHD) consensus group. This article will provide an insight into the diagnostic criteria of oGVHD, its classification, and clinical severity grading scales. The inflammatory process in oGVHD can involve the entire ocular surface including the eyelids, meibomian gland, corneal, conjunctiva, and lacrimal system. The varied clinical presentations and treatment strategies employed to manage them have been discussed in the present study. The recent advances in ocular surface imaging in oGVHD patients such as the use of meibography and in vivo confocal microscopy may help in early diagnosis and prognostication of the disease. Researching tear proteomics and identification of novel potential tear biomarkers in oGVHD patients is an exciting field as they may help in objectively diagnosing the disease and monitoring the response to treatment.
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Affiliation(s)
- Sridevi Nair
- Cornea, Cataract & Refractive Surgery Services, Dr R P Centre, All India Institute of Medical Sciences, New Delhi, India
| | - Murugesan Vanathi
- Cornea, Cataract & Refractive Surgery Services, Dr R P Centre, All India Institute of Medical Sciences, New Delhi, India
| | - Ritika Mukhija
- Cornea, Cataract & Refractive Surgery Services, Dr R P Centre, All India Institute of Medical Sciences, New Delhi, India
| | - Radhika Tandon
- Cornea, Cataract & Refractive Surgery Services, Dr R P Centre, All India Institute of Medical Sciences, New Delhi, India
| | - Sandeep Jain
- Department of Ophthalmology, University of Chicago, USA
| | - Yoko Ogawa
- Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan
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18
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Appenteng Osae E, Steven P. Meibomian Gland Dysfunction in Ocular Graft vs. Host Disease: A Need for Pre-Clinical Models and Deeper Insights. Int J Mol Sci 2021; 22:ijms22073516. [PMID: 33805326 PMCID: PMC8036656 DOI: 10.3390/ijms22073516] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 03/25/2021] [Accepted: 03/27/2021] [Indexed: 12/20/2022] Open
Abstract
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.
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Affiliation(s)
- Eugene Appenteng Osae
- College of Optometry, University of Houston, Houston, TX 77004, USA
- Correspondence: ; Tel.: +1-346-317-6273
| | - Philipp Steven
- Department of Ophthalmology, Division for Dry-Eye and Ocular GVHD, Medical Faculty, University of Cologne, 50923 Cologne, Germany;
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19
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Jacobs DS, Carrasquillo KG, Cottrell PD, Fernández-Velázquez FJ, Gil-Cazorla R, Jalbert I, Pucker AD, Riccobono K, Robertson DM, Szczotka-Flynn L, Speedwell L, Stapleton F. CLEAR - Medical use of contact lenses. Cont Lens Anterior Eye 2021; 44:289-329. [PMID: 33775381 DOI: 10.1016/j.clae.2021.02.002] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 02/01/2021] [Indexed: 12/11/2022]
Abstract
The medical use of contact lenses is a solution for many complex ocular conditions, including high refractive error, irregular astigmatism, primary and secondary corneal ectasia, disfiguring disease, and ocular surface disease. The development of highly oxygen permeable soft and rigid materials has extended the suitability of contact lenses for such applications. There is consistent evidence that bandage soft contact lenses, particularly silicone hydrogel lenses, improve epithelial healing and reduce pain in persistent epithelial defects, after trauma or surgery, and in corneal dystrophies. Drug delivery applications of contact lens hold promise for improving topical therapy. Modern scleral lens practice has achieved great success for both visual rehabilitation and therapeutic applications, including those requiring retention of a tear reservoir or protection from an adverse environment. This report offers a practical and relevant summary of the current evidence for the medical use of contact lenses for all eye care professionals including optometrists, ophthalmologists, opticians, and orthoptists. Topics covered include indications for use in both acute and chronic conditions, lens selection, patient selection, wear and care regimens, and recommended aftercare schedules. Prevention, presentation, and management of complications of medical use are reviewed.
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Affiliation(s)
- Deborah S Jacobs
- Massachusetts Eye & Ear, Cornea and Refractive Surgery Service, Harvard Medical School, Boston, MA, USA.
| | | | | | | | | | | | | | | | | | - Loretta Szczotka-Flynn
- Department of Ophthalmology & Visual Science, Case Western Reserve University, Cleveland, OH, USA
| | - Lynne Speedwell
- Great Ormond Street Hospital for Children NHS Trust, Moorfields Eye Hospital, London, UK
| | - Fiona Stapleton
- School of Optometry and Vision Science, UNSW Sydney, Australia
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20
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Efficacy and Safety of 1% Progesterone Gel to the Forehead for Ocular Chronic Graft-versus-Host Disease. Transplant Cell Ther 2021; 27:433.e1-433.e8. [PMID: 33942724 DOI: 10.1016/j.jtct.2021.02.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 02/06/2021] [Accepted: 02/07/2021] [Indexed: 11/24/2022]
Abstract
There is no Food and Drug Administration-approved treatments for ocular chronic graft-versus-host disease (oGVHD) to date, and current therapeutic options are limited. Forehead application of 1% progesterone gel provides corneal antinociception in preclinical models, suggesting it may be useful in alleviating ocular irritations. This study was conducted to evaluate the efficacy and safety of 1% progesterone gel in treating moderate to severe symptomatic oGVHD. Thirty-three patients with oGVHD following allogeneic stem cell transplantation were enrolled in this single-center, sponsor-initiated, prospective exploratory randomized double-masked placebo-controlled phase II clinical trial. The inclusion criteria included a National Institutes of Health consensus score of ≥2, moderate to severe ocular discomfort level, and receipt of a stable immunosuppression regimen. Twenty-one of the 22 patients in the progesterone arm and all 11 patients in the placebo arm completed the course of twice-daily forehead drug application for 10 weeks. The changes from baseline of self-reported ocular symptom scores and physician-recorded cornea fluorescein staining scores were analyzed using mixed-model repeated-measures regression model in an intention-to-treat population. The 33 patients included 12 women and 21 men, with a median age of 66 years (range, 24 to 75 years). At 10 weeks, there was a significant reduction in ocular symptoms from baseline in the progesterone group compared with the placebo group in symptom frequency (-30.7 versus -2.2; P < .001) and severity (-19.8 versus +1.6; P = .005). At 10 weeks, there was also greater reduction of cornea fluorescein staining centrally (-1.2 versus +.1; P = .001) and inferiorly (-1.4 versus -0.2; P = .005). No difference was noted in superior cornea staining. There were no severe adverse events in the progesterone group. Forehead application of 1% progesterone gel significantly improved ocular signs and symptoms within 10 weeks. It appears to be a safe and effective new therapy for oGVHD, and a novel mechanism for neuroaxis drug delivery. A multicenter phase III clinical trial is planned for further validation.
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Sahle FF, Kim S, Niloy KK, Tahia F, Fili CV, Cooper E, Hamilton DJ, Lowe TL. Nanotechnology in regenerative ophthalmology. Adv Drug Deliv Rev 2019; 148:290-307. [PMID: 31707052 PMCID: PMC7474549 DOI: 10.1016/j.addr.2019.10.006] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 10/29/2019] [Accepted: 10/30/2019] [Indexed: 12/18/2022]
Abstract
In recent years, regenerative medicine is gaining momentum and is giving hopes for restoring function of diseased, damaged, and aged tissues and organs and nanotechnology is serving as a catalyst. In the ophthalmology field, various types of allogenic and autologous stem cells have been investigated to treat some ocular diseases due to age-related macular degeneration, glaucoma, retinitis pigmentosa, diabetic retinopathy, and corneal and lens traumas. Nanomaterials have been utilized directly as nanoscaffolds for these stem cells to promote their adhesion, proliferation and differentiation or indirectly as vectors for various genes, tissue growth factors, cytokines and immunosuppressants to facilitate cell reprogramming or ocular tissue regeneration. In this review, we reviewed various nanomaterials used for retina, cornea, and lens regenerations, and discussed the current status and future perspectives of nanotechnology in tracking cells in the eye and personalized regenerative ophthalmology. The purpose of this review is to provide comprehensive and timely insights on the emerging field of nanotechnology for ocular tissue engineering and regeneration.
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Affiliation(s)
- Fitsum Feleke Sahle
- Department of Pharmaceutical Sciences, University of Tennessee Health Sciences Center, Memphis, TN 38163, USA
| | - Sangyoon Kim
- Department of Pharmaceutical Sciences, University of Tennessee Health Sciences Center, Memphis, TN 38163, USA
| | - Kumar Kulldeep Niloy
- Department of Pharmaceutical Sciences, University of Tennessee Health Sciences Center, Memphis, TN 38163, USA
| | - Faiza Tahia
- Department of Pharmaceutical Sciences, University of Tennessee Health Sciences Center, Memphis, TN 38163, USA
| | - Cameron V Fili
- Department of Comparative Medicine, University of Tennessee Health Sciences Center, Memphis, TN 38163, USA
| | - Emily Cooper
- Department of Pharmaceutical Sciences, University of Tennessee Health Sciences Center, Memphis, TN 38163, USA
| | - David J Hamilton
- Department of Comparative Medicine, University of Tennessee Health Sciences Center, Memphis, TN 38163, USA
| | - Tao L Lowe
- Department of Pharmaceutical Sciences, University of Tennessee Health Sciences Center, Memphis, TN 38163, USA.
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22
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An S, Raju I, Surenkhuu B, Kwon JE, Gulati S, Karaman M, Pradeep A, Sinha S, Mun C, Jain S. Neutrophil extracellular traps (NETs) contribute to pathological changes of ocular graft-vs.-host disease (oGVHD) dry eye: Implications for novel biomarkers and therapeutic strategies. Ocul Surf 2019; 17:589-614. [PMID: 30965123 PMCID: PMC6721977 DOI: 10.1016/j.jtos.2019.03.010] [Citation(s) in RCA: 78] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2019] [Revised: 03/27/2019] [Accepted: 03/28/2019] [Indexed: 12/18/2022]
Abstract
PURPOSE To investigate the role of neutrophil extracellular traps (NETs) and NET-associated proteins in the pathogenesis of oGVHD and whether dismantling of NETs with heparin reduces those changes. METHODS Ocular surface washings from oGVHD patients and healthy subjects were analyzed. Isolated peripheral blood human neutrophils were stimulated to generate NETs and heparinized NETs. We performed in vitro experiments using cell lines (corneal epithelial, conjunctival fibroblast, meibomian gland (MG) epithelial and T cells), and in vivo experiments using murine models, and compared the effects of NETs, heparinized NETs, NET-associated proteins and neutralizing antibodies to NET-associated proteins. RESULTS Neutrophils, exfoliated epithelial cells, NETs and NET-associated proteins (extracellular DNA, Neutrophil Elastase, Myeloperoxidase, Oncostatin M (OSM), Neutrophil gelatinase-associated lipocalin (NGAL) and LIGHT/TNFSF14) are present in ocular surface washings (OSW) and mucocellular aggregates (MCA). Eyes with high number of neutrophils in OSW have more severe signs and symptoms of oGVHD. NETs (and OSM) cause epitheliopathy in murine corneas. NETs (and LIGHT/TNFSF14) increase proliferation of T cells. NETs (and NGAL) inhibit proliferation and differentiation of MG epithelial cells. NETs enhance proliferation and myofibroblast transformation of conjunctival fibroblasts. Sub-anticoagulant dose Heparin (100 IU/mL) dismantles NETs and reduces epithelial, fibroblast, T cell and MG cell changes induced by NETs. CONCLUSION NETs and NET-associated proteins contribute to the pathological changes of oGVHD (corneal epitheliopathy, conjunctival cicatrization, ocular surface inflammation and meibomian gland disease). Our data points to the potential of NET-associated proteins (OSM or LIGHT/TNFSF14) to serve as biomarkers and NET-dismantling biologics (heparin eye drops) as treatment for oGVHD.
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Affiliation(s)
- Seungwon An
- Cornea Translational Biology Laboratory, Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Ilangovan Raju
- Cornea Translational Biology Laboratory, Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Bayasgalan Surenkhuu
- Cornea Translational Biology Laboratory, Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Ji-Eun Kwon
- Cornea Translational Biology Laboratory, Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Shilpa Gulati
- Cornea Translational Biology Laboratory, Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Muge Karaman
- Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Anubhav Pradeep
- Cornea Translational Biology Laboratory, Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | | | - Christine Mun
- Cornea Translational Biology Laboratory, Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Sandeep Jain
- Cornea Translational Biology Laboratory, Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, 60612, USA.
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Ocular surface system alterations in ocular graft-versus-host disease: all the pieces of the complex puzzle. Graefes Arch Clin Exp Ophthalmol 2019; 257:1341-1351. [PMID: 30944986 DOI: 10.1007/s00417-019-04301-6] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Revised: 03/11/2019] [Accepted: 03/20/2019] [Indexed: 01/01/2023] Open
Abstract
PURPOSE Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cells transplantation, occurring in about half of transplanted patients. This condition seems to be the result of a progressive immune-mediated damage that can involve various tissues, including the eyes. The ocular surface system is the ocular structure most frequently impaired, and dry eye disease is considered the hallmark of ocular GVHD. Given the increasing prevalence and the frequent severe involvement of the ocular surface with vision-threatening complications, ocular GVHD represents a current diagnostic and therapeutic challenge. The purpose of this literature review is to describe all the clinical manifestations occurring in the setting of ocular GVHD, and to further report the outcomes of conventional and novel therapies. METHODS A literature search about ocular GVHD was performed in PubMed, Scopus, Medline databases, and ClinicalTrials.gov as well as through the reference lists of identified publications until January 2019. We have included RCTs, prospective observational studies, prospective and retrospective cohort studies, pilot studies, and review articles. RESULTS Overall, 107 articles, 3 book chapters, and 6 ongoing registered clinical trials were collected and analyzed. Ocular GVHD can affect all the structures of the entire ocular surface system, including lacrimal and meibomian glands, cornea, conjunctiva, eyelids, nasolacrimal duct, and tears. Current medical treatment is mainly focused on lubrication and control of drainage, tear evaporation, and ocular surface inflammation. Surgical treatment may be necessary in severe, recalcitrant, or complicated cases. Amniotic membrane and tectonic keratoplasty can be valid options to restore the integrity of the cornea. Recently, conjunctival and limbal transplantation from the same living-related bone marrow donor has been proposed to manage both dry eye and limbal stem cell deficiency, without any risk of immunologic rejection. CONCLUSION This review provides an up-to-date analysis on clinical findings and current and future management of ocular GVHD. A correct and prompt diagnosis along with an appropriate and aggressive treatment are fundamental for avoiding the occurrence of vision-threatening complications.
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Best AL, Labetoulle M, Legrand M, M'garrech M, Barreau E, Rousseau A. [Punctal and canalicular plugs: Indications, efficacy and safety (French translation of the article)]. J Fr Ophtalmol 2019; 42:404-414. [PMID: 30879835 DOI: 10.1016/j.jfo.2018.10.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Revised: 10/08/2018] [Accepted: 10/12/2018] [Indexed: 10/27/2022]
Abstract
Lacrimal occlusion with punctal or canalicular plugs have been used to treat dry eye disease for more than 40 years. Indeed, punctal plugs constitute a safe and effective tool to retain the natural tear film and prolong the effect of tear substitutes. A wide variety of plugs is available, differing in their design, location (punctal versus canalicular) and their resorbability. There indications have increasingly broadened, and they are now one of the treatment options for numerous ocular surface diseases. Current research focuses on using punctal plugs for extended delivery of drugs to the ocular surface. This review addresses physiology of lacrimal drainage, available models of punctal plugs, their indications, practical details of prescribing and placing punctal and canalicular plugs, and possible complications.
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Affiliation(s)
- A-L Best
- Service d'ophtalmologie, centre de référence maladies rares en ophtalmologie OPHTARA, hôpital Bicêtre, université Paris-Sud, DHU vision et handicap, Assistance publique-Hôpitaux de Paris, 78, rue du Général Leclerc, 94275 Le Kremlin-Bicêtre cedex, France
| | - M Labetoulle
- Service d'ophtalmologie, centre de référence maladies rares en ophtalmologie OPHTARA, hôpital Bicêtre, université Paris-Sud, DHU vision et handicap, Assistance publique-Hôpitaux de Paris, 78, rue du Général Leclerc, 94275 Le Kremlin-Bicêtre cedex, France; Immunologie des maladies virales et maladies auto-immunes (IMVA/Infrastructure IDMIT) UMR 1184, CEA, 92260 Fontenay-aux-Roses, France
| | - M Legrand
- Service d'ophtalmologie, centre de référence maladies rares en ophtalmologie OPHTARA, hôpital Bicêtre, université Paris-Sud, DHU vision et handicap, Assistance publique-Hôpitaux de Paris, 78, rue du Général Leclerc, 94275 Le Kremlin-Bicêtre cedex, France
| | - M M'garrech
- Service d'ophtalmologie, centre de référence maladies rares en ophtalmologie OPHTARA, hôpital Bicêtre, université Paris-Sud, DHU vision et handicap, Assistance publique-Hôpitaux de Paris, 78, rue du Général Leclerc, 94275 Le Kremlin-Bicêtre cedex, France
| | - E Barreau
- Service d'ophtalmologie, centre de référence maladies rares en ophtalmologie OPHTARA, hôpital Bicêtre, université Paris-Sud, DHU vision et handicap, Assistance publique-Hôpitaux de Paris, 78, rue du Général Leclerc, 94275 Le Kremlin-Bicêtre cedex, France
| | - A Rousseau
- Service d'ophtalmologie, centre de référence maladies rares en ophtalmologie OPHTARA, hôpital Bicêtre, université Paris-Sud, DHU vision et handicap, Assistance publique-Hôpitaux de Paris, 78, rue du Général Leclerc, 94275 Le Kremlin-Bicêtre cedex, France; Immunologie des maladies virales et maladies auto-immunes (IMVA/Infrastructure IDMIT) UMR 1184, CEA, 92260 Fontenay-aux-Roses, France.
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25
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Best AL, Labetoulle M, Legrand M, M'garrech M, Barreau E, Rousseau A. Punctal and canalicular plugs: Indications, efficacy and safety. J Fr Ophtalmol 2019; 42:e95-e104. [PMID: 30692031 DOI: 10.1016/j.jfo.2018.12.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2018] [Revised: 12/10/2018] [Accepted: 12/14/2018] [Indexed: 10/27/2022]
Abstract
Lacrimal occlusion with punctal or canalicular plugs have been used to treat dry eye disease for more than 40 years. Indeed, punctal plugs constitute a safe and effective tool to retain the natural tear film and prolong the effect of tear substitutes. A wide variety of plugs is available, differing in their design, location (punctal versus canalicular) and their resorbability. There indications have increasingly broadened, and they are now one of the treatment options for numerous ocular surface diseases. Current research focuses on using punctal plugs for extended delivery of drugs to the ocular surface. This review addresses physiology of lacrimal drainage, available models of punctal plugs, their indications, practical details of prescribing and placing punctal and canalicular plugs, and possible complications.
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Affiliation(s)
- A-L Best
- Ophthalmology Service, Hôpital Bicêtre, Assistance publique-Hôpitaux de Paris, Université Paris-Sud, Division of Vision and Disabilities, OPHTARA rare eye disease, 78, rue du Général-Leclerc, 94275 Le Kremlin-Bicêtre cedex, France
| | - M Labetoulle
- Ophthalmology Service, Hôpital Bicêtre, Assistance publique-Hôpitaux de Paris, Université Paris-Sud, Division of Vision and Disabilities, OPHTARA rare eye disease, 78, rue du Général-Leclerc, 94275 Le Kremlin-Bicêtre cedex, France; Viral and autoimmune disease immunology (IMVA/Infrastructure IDMIT) UMR 1184, CEA, 92260 Fontenay-aux-Roses, France
| | - M Legrand
- Ophthalmology Service, Hôpital Bicêtre, Assistance publique-Hôpitaux de Paris, Université Paris-Sud, Division of Vision and Disabilities, OPHTARA rare eye disease, 78, rue du Général-Leclerc, 94275 Le Kremlin-Bicêtre cedex, France
| | - M M'garrech
- Ophthalmology Service, Hôpital Bicêtre, Assistance publique-Hôpitaux de Paris, Université Paris-Sud, Division of Vision and Disabilities, OPHTARA rare eye disease, 78, rue du Général-Leclerc, 94275 Le Kremlin-Bicêtre cedex, France
| | - E Barreau
- Ophthalmology Service, Hôpital Bicêtre, Assistance publique-Hôpitaux de Paris, Université Paris-Sud, Division of Vision and Disabilities, OPHTARA rare eye disease, 78, rue du Général-Leclerc, 94275 Le Kremlin-Bicêtre cedex, France
| | - A Rousseau
- Ophthalmology Service, Hôpital Bicêtre, Assistance publique-Hôpitaux de Paris, Université Paris-Sud, Division of Vision and Disabilities, OPHTARA rare eye disease, 78, rue du Général-Leclerc, 94275 Le Kremlin-Bicêtre cedex, France; Viral and autoimmune disease immunology (IMVA/Infrastructure IDMIT) UMR 1184, CEA, 92260 Fontenay-aux-Roses, France.
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26
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Giannaccare G, Bernabei F, Pellegrini M, Arpinati M, Bonifazi F, Sessa M, Versura P, Campos E. Eyelid metrics assessment in patients with chronic ocular graft versus-host disease. Ocul Surf 2019; 17:98-103. [DOI: 10.1016/j.jtos.2018.10.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Revised: 10/04/2018] [Accepted: 10/11/2018] [Indexed: 01/07/2023]
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27
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Byun YS, Yoo YS, Kang MJ, Whang WJ, Na KS, Mok JW, Joo CK. Marked infiltration of neutrophils at the upper palpebral conjunctiva in patients with chronic graft-versus-host disease. Ocul Surf 2018; 17:295-302. [PMID: 30578957 DOI: 10.1016/j.jtos.2018.12.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Revised: 10/25/2018] [Accepted: 12/18/2018] [Indexed: 10/27/2022]
Abstract
PURPOSE Neutrophils may be involved in the local pathophysiology of chronic graft-versus-host disease (cGVHD). We evaluated neutrophil infiltration in cGVHD using conjunctival impression cytology (IC) and its clinical correlation with ocular surface status and neutrophil enzyme levels in tears. METHODS This cross-sectional observational study included 76 patients with cGVHD. The ocular surface was assessed for the tear break-up time, Schirmer I test, corneal and conjunctival staining score, meiboscore, and the ocular surface disease index questionnaire. Conjunctival IC was performed at the temporal, superior bulbar, and upper palpebral conjunctiva, and the number of neutrophils (cells/high power field [HPF]) was calculated. Neutrophil elastase (NE), myeloperoxidase (MPO), and matrix metalloperoxidase-8 and -9 levels in tear washes were measured in 20 patients. RESULTS The number of neutrophils was significantly greater at the upper palpebral conjunctiva (median [range], 16.5 [0 to 147] cells/HPF) than at the temporal and superior bulbar conjunctiva (0 [0 to 70] and 0 [0 to 105] cells/HPF; P < 0.0001). The number of neutrophils at the upper palpebral conjunctiva showed moderate correlations with the corneal staining score and the NE and MPO levels in tears (r = 0.668, 0.553, and 0.563, respectively; P < 0.0001, P = 0.014, and 0.012). CONCLUSIONS Our results suggest that neutrophils at the upper palpebral conjunctiva associate with the clinical manifestations and inflammatory status of the ocular surface in cGVHD. Conjunctival neutrophils should be addressed when assessing the inflammatory activity of ocular cGVHD and exploring its pathogenesis.
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Affiliation(s)
- Yong-Soo Byun
- Department of Ophthalmology, Seoul St. Mary's Hospital, College of Medicine, Catholic University of Korea, Republic of Korea; Catholic Institute for Visual Science, College of Medicine, Catholic University of Korea, Republic of Korea
| | - Young-Sik Yoo
- Catholic Institute for Visual Science, College of Medicine, Catholic University of Korea, Republic of Korea
| | - Min-Ji Kang
- Department of Ophthalmology, Seoul St. Mary's Hospital, College of Medicine, Catholic University of Korea, Republic of Korea; Catholic Institute for Visual Science, College of Medicine, Catholic University of Korea, Republic of Korea
| | - Woong-Joo Whang
- Department of Ophthalmology, Yeuido St. Mary's Hospital, College of Medicine, Catholic University of Korea, Republic of Korea
| | - Kyung-Sun Na
- Department of Ophthalmology, Yeuido St. Mary's Hospital, College of Medicine, Catholic University of Korea, Republic of Korea
| | - Jee-Won Mok
- Catholic Institute for Visual Science, College of Medicine, Catholic University of Korea, Republic of Korea
| | - Choun-Ki Joo
- Department of Ophthalmology, Seoul St. Mary's Hospital, College of Medicine, Catholic University of Korea, Republic of Korea; Catholic Institute for Visual Science, College of Medicine, Catholic University of Korea, Republic of Korea.
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Update on the Surgical Reconstruction of Ocular Surface in Eyes with Limbal Stem Cell Deficiency. CURRENT OPHTHALMOLOGY REPORTS 2018. [DOI: 10.1007/s40135-018-0187-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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Le Q, Xu J, Deng SX. The diagnosis of limbal stem cell deficiency. Ocul Surf 2018; 16:58-69. [PMID: 29113917 PMCID: PMC5844504 DOI: 10.1016/j.jtos.2017.11.002] [Citation(s) in RCA: 125] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Revised: 08/24/2017] [Accepted: 11/03/2017] [Indexed: 12/15/2022]
Abstract
Limbal stem cells (LSCs) maintain the normal homeostasis and wound healing of corneal epithelium. Limbal stem cell deficiency (LSCD) is a pathologic condition that results from the dysfunction and/or an insufficient quantity of LSCs. The diagnosis of LSCD has been made mainly based on medical history and clinical signs, which often are not specific to LSCD. Methods to stage the severity of LSCD have been lacking. With the application of newly developed ocular imaging modalities and molecular methods as diagnostic tools, standardized quantitative criteria for the staging of LSCD can be established. Because of these recent advancements, effective patient-specific therapy for different stages of LSCD may be feasible.
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Affiliation(s)
- Qihua Le
- Stein Eye Institute, Cornea Division, David Geffen School of Medicine, University of California, Los Angeles, USA; Department of Ophthalmology, Eye & ENT Hospital of Fudan University, Shanghai 200031, China
| | - Jianjiang Xu
- Department of Ophthalmology, Eye & ENT Hospital of Fudan University, Shanghai 200031, China
| | - Sophie X Deng
- Stein Eye Institute, Cornea Division, David Geffen School of Medicine, University of California, Los Angeles, USA.
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30
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Cheung AY, Genereux BM, Auteri NJ, Sarnicola E, Govil A, Holland EJ. Conjunctival-limbal allografts in graft-versus-host disease using same HLA-identical bone marrow transplantation donor. Can J Ophthalmol 2017; 53:e120-e122. [PMID: 29784177 DOI: 10.1016/j.jcjo.2017.09.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Accepted: 09/05/2017] [Indexed: 11/29/2022]
Affiliation(s)
- Albert Y Cheung
- Cincinnati Eye Institute, Cincinnati, OH; Department of Ophthalmology, University of Cincinnati, Cincinnati, OH
| | | | | | - Enrica Sarnicola
- Cincinnati Eye Institute, Cincinnati, OH; Department of Medicine Surgery and Neuroscience, University of Siena, Siena, Italy
| | - Amit Govil
- Division of Nephrology and Hypertension, University of Cincinnati, Cincinnati, OH
| | - Edward J Holland
- Cincinnati Eye Institute, Cincinnati, OH; Department of Ophthalmology, University of Cincinnati, Cincinnati, OH.
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Kuony A, Michon F. Epithelial Markers aSMA, Krt14, and Krt19 Unveil Elements of Murine Lacrimal Gland Morphogenesis and Maturation. Front Physiol 2017; 8:739. [PMID: 29033846 PMCID: PMC5627580 DOI: 10.3389/fphys.2017.00739] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2017] [Accepted: 09/11/2017] [Indexed: 12/21/2022] Open
Abstract
As an element of the lacrimal apparatus, the lacrimal gland (LG) produces the aqueous part of the tear film, which protects the eye surface. Therefore, a defective LG can lead to serious eyesight impairment. Up to now, little is known about LG morphogenesis and subsequent maturation. In this study, we delineated elements of the cellular and molecular events involved in LG formation by using three epithelial markers, namely aSMA, Krt14, and Krt19. While aSMA marked a restricted epithelial population of the terminal end buds (TEBs) in the forming LG, Krt14 was found in the whole embryonic LG epithelial basal cell layer. Interestingly, Krt19 specifically labeled the presumptive ductal domain and subsequently, the luminal cell layer. By combining these markers, the Fucci reporter mouse strain and genetic fate mapping of the Krt14+ population, we demonstrated that LG epithelium expansion is fuelled by a patterned cell proliferation, and to a lesser extent by epithelial reorganization and possible mesenchymal-to-epithelial transition. We pointed out that this epithelial reorganization, which is associated with apoptosis, regulated the lumen formation. Finally, we showed that the inhibition of Notch signaling prevented the ductal identity from setting, and led to a LG covered by ectopic TEBs. Taken together our results bring a deeper understanding on LG morphogenesis, epithelial domain identity, and organ expansion.
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Affiliation(s)
- Alison Kuony
- Developmental Biology Program, Institute of Biotechnology, University of HelsinkiHelsinki, Finland
| | - Frederic Michon
- Developmental Biology Program, Institute of Biotechnology, University of HelsinkiHelsinki, Finland
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Abstract
PURPOSE OF REVIEW The aim of this review is to describe the underlying mechanisms of corneal epithelial homeostasis in addition to illustrating the vital role of the limbal epithelial stem cells (LESCs) and the limbal niche in epithelial regeneration and wound healing. RECENT FINDINGS The shedded corneal epithelial cells are constantly replenished by the LESCs which give rise to epithelial cells that proliferate, differentiate, and migrate centripetally. While some recent studies have proposed that epithelial stem cells may also be present in the central cornea, the predominant location for the stem cells is the limbus. The limbal niche is the specialized microenvironment consisting of cells, extracellular matrix, and signaling molecules that are essential for the function of LESCs. Disturbances to limbal niche can result in LESC dysfunction; therefore, limbal stem cell deficiency should also be considered a limbal niche deficiency. Current and in-development therapeutic strategies are aimed at restoring the limbal niche, by medical and/or surgical treatments, administration of trophic factors, and cell based therapies. SUMMARY The corneal epithelium is constantly replenished by LESCs that are housed within the limbal niche. The limbal niche is the primary determinant of the LESC function and novel therapeutic approaches should be focused on regeneration of this microenvironment.
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