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Frutos-Rincón L, Gómez-Sánchez JA, Íñigo-Portugués A, Acosta MC, Gallar J. An Experimental Model of Neuro-Immune Interactions in the Eye: Corneal Sensory Nerves and Resident Dendritic Cells. Int J Mol Sci 2022; 23:ijms23062997. [PMID: 35328417 PMCID: PMC8951464 DOI: 10.3390/ijms23062997] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 02/28/2022] [Accepted: 03/04/2022] [Indexed: 12/04/2022] Open
Abstract
The cornea is an avascular connective tissue that is crucial, not only as the primary barrier of the eye but also as a proper transparent refractive structure. Corneal transparency is necessary for vision and is the result of several factors, including its highly organized structure, the physiology of its few cellular components, the lack of myelinated nerves (although it is extremely innervated), the tightly controlled hydration state, and the absence of blood and lymphatic vessels in healthy conditions, among others. The avascular, immune-privileged tissue of the cornea is an ideal model to study the interactions between its well-characterized and dense sensory nerves (easily accessible for both focal electrophysiological recording and morphological studies) and the low number of resident immune cell types, distinguished from those cells migrating from blood vessels. This paper presents an overview of the corneal structure and innervation, the resident dendritic cell (DC) subpopulations present in the cornea, their distribution in relation to corneal nerves, and their role in ocular inflammatory diseases. A mouse model in which sensory axons are constitutively labeled with tdTomato and DCs with green fluorescent protein (GFP) allows further analysis of the neuro-immune crosstalk under inflammatory and steady-state conditions of the eye.
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Affiliation(s)
- Laura Frutos-Rincón
- Instituto de Neurociencias, Universidad Miguel Hernández—Consejo Superior de Investigaciones Científicas, 03550 San Juan de Alicante, Spain; (L.F.-R.); (A.Í.-P.); (M.C.A.); (J.G.)
- The European University of Brain and Technology-NeurotechEU, 03550 San Juan de Alicante, Spain
| | - José Antonio Gómez-Sánchez
- Instituto de Neurociencias, Universidad Miguel Hernández—Consejo Superior de Investigaciones Científicas, 03550 San Juan de Alicante, Spain; (L.F.-R.); (A.Í.-P.); (M.C.A.); (J.G.)
- Correspondence: ; Tel.: +34-965-91-9594
| | - Almudena Íñigo-Portugués
- Instituto de Neurociencias, Universidad Miguel Hernández—Consejo Superior de Investigaciones Científicas, 03550 San Juan de Alicante, Spain; (L.F.-R.); (A.Í.-P.); (M.C.A.); (J.G.)
| | - M. Carmen Acosta
- Instituto de Neurociencias, Universidad Miguel Hernández—Consejo Superior de Investigaciones Científicas, 03550 San Juan de Alicante, Spain; (L.F.-R.); (A.Í.-P.); (M.C.A.); (J.G.)
- The European University of Brain and Technology-NeurotechEU, 03550 San Juan de Alicante, Spain
| | - Juana Gallar
- Instituto de Neurociencias, Universidad Miguel Hernández—Consejo Superior de Investigaciones Científicas, 03550 San Juan de Alicante, Spain; (L.F.-R.); (A.Í.-P.); (M.C.A.); (J.G.)
- The European University of Brain and Technology-NeurotechEU, 03550 San Juan de Alicante, Spain
- Instituto de Investigación Biomédica y Sanitaria de Alicante, 03010 Alicante, Spain
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Jamali A, Kenyon B, Ortiz G, Abou-Slaybi A, Sendra VG, Harris DL, Hamrah P. Plasmacytoid dendritic cells in the eye. Prog Retin Eye Res 2020; 80:100877. [PMID: 32717378 DOI: 10.1016/j.preteyeres.2020.100877] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 05/28/2020] [Accepted: 06/05/2020] [Indexed: 02/07/2023]
Abstract
Plasmacytoid dendritic cells (pDCs) are a unique subpopulation of immune cells, distinct from classical dendritic cells. pDCs are generated in the bone marrow and following development, they typically home to secondary lymphoid tissues. While peripheral tissues are generally devoid of pDCs during steady state, few tissues, including the lung, kidney, vagina, and in particular ocular tissues harbor resident pDCs. pDCs were originally appreciated for their potential to produce large quantities of type I interferons in viral immunity. Subsequent studies have now unraveled their pivotal role in mediating immune responses, in particular in the induction of tolerance. In this review, we summarize our current knowledge on pDCs in ocular tissues in both mice and humans, in particular in the cornea, limbus, conjunctiva, choroid, retina, and lacrimal gland. Further, we will review our current understanding on the significance of pDCs in ameliorating inflammatory responses during herpes simplex virus keratitis, sterile inflammation, and corneal transplantation. Moreover, we describe their novel and pivotal neuroprotective role, their key function in preserving corneal angiogenic privilege, as well as their potential application as a cell-based therapy for ocular diseases.
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Affiliation(s)
- Arsia Jamali
- Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA; Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA
| | - Brendan Kenyon
- Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA; Program in Neuroscience, Graduate School of Biomedical Sciences, Tufts University, Boston, MA, USA
| | - Gustavo Ortiz
- Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA; Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA
| | - Abdo Abou-Slaybi
- Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA; Program in Immunology, Graduate School of Biomedical Sciences, Tufts University, Boston, MA, USA
| | - Victor G Sendra
- Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA; Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA
| | - Deshea L Harris
- Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA; Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA
| | - Pedram Hamrah
- Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA; Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA; Program in Neuroscience, Graduate School of Biomedical Sciences, Tufts University, Boston, MA, USA; Program in Immunology, Graduate School of Biomedical Sciences, Tufts University, Boston, MA, USA; Cornea Service, Tufts New England Eye Center, Boston, MA, USA.
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Immune Checkpoints Contribute Corneal Immune Privilege: Implications for Dry Eye Associated with Checkpoint Inhibitors. Int J Mol Sci 2020; 21:ijms21113962. [PMID: 32486493 PMCID: PMC7312178 DOI: 10.3390/ijms21113962] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 05/30/2020] [Accepted: 05/30/2020] [Indexed: 12/22/2022] Open
Abstract
The eye is provided with immune protection against pathogens in a manner that greatly reduces the threat of inflammation-induced vision loss. Immune-mediated inflammation and allograft rejection are greatly reduced in the eye, a phenomenon called 'immune privilege'. Corneal tissue has inherent immune privilege properties with underlying three mechanisms: (1) anatomical, cellular, and molecular barriers in the cornea; (2) an immunosuppressive microenvironment; and (3) tolerance related to regulatory T cells and anterior chamber-associated immune deviation. This review describes the molecular mechanisms of the immunosuppressive microenvironment and regulatory T cells in the cornea that have been elucidated from animal models of ocular inflammation, especially those involving corneal transplantation, it also provides an update on immune checkpoint molecules in corneal and systemic immune regulation, and its relevance for dry eye associated with checkpoint inhibitor therapy.
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Holan V, Hermankova B, Krulova M, Zajicova A. Cytokine interplay among the diseased retina, inflammatory cells and mesenchymal stem cells - a clue to stem cell-based therapy. World J Stem Cells 2019; 11:957-967. [PMID: 31768222 PMCID: PMC6851013 DOI: 10.4252/wjsc.v11.i11.957] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 09/02/2019] [Accepted: 09/14/2019] [Indexed: 02/06/2023] Open
Abstract
Retinal degenerative disorders, such as diabetic retinopathy, retinitis pigmentosa, age-related macular degeneration or glaucoma, represent the most common causes of loss of vision and blindness. In spite of intensive research, treatment options to prevent, stop or cure these diseases are limited. Newer therapeutic approaches are offered by stem cell-based therapy. To date, various types of stem cells have been evaluated in a range of models. Among them, mesenchymal stem/stromal cells (MSCs) derived from bone marrow or adipose tissue and used as autologous cells have been proposed to have the potential to attenuate the negative manifestations of retinal diseases. MSCs delivered to the vicinity of the diseased retina can exert local anti-inflammatory and repair-promoting/regenerative effects on retinal cells. However, MSCs also produce numerous factors that could have negative impacts on retinal regeneration. The secretory activity of MSCs is strongly influenced by the cytokine environment. Therefore, the interactions among the molecules produced by the diseased retina, cytokines secreted by inflammatory cells and factors produced by MSCs will decide the development and propagation of retinal diseases. Here we discuss the interactions among cytokines and other factors in the environment of the diseased retina treated by MSCs, and we present results supporting immunoregulatory and trophic roles of molecules secreted in the vicinity of the retina during MSC-based therapy.
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Affiliation(s)
- Vladimir Holan
- Department of Transplantation Immunology, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague 14220, Czech Republic
- Department of Cell Biology, Faculty of Science, Charles University, Prague 12843, Czech Republic
| | - Barbora Hermankova
- Department of Transplantation Immunology, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague 14220, Czech Republic
- Department of Cell Biology, Faculty of Science, Charles University, Prague 12843, Czech Republic
| | - Magdalena Krulova
- Department of Transplantation Immunology, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague 14220, Czech Republic
- Department of Cell Biology, Faculty of Science, Charles University, Prague 12843, Czech Republic
| | - Alena Zajicova
- Department of Transplantation Immunology, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague 14220, Czech Republic
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Ben M’Barek K, Habeler W, Regent F, Monville C. Developing Cell-Based Therapies for RPE-Associated Degenerative Eye Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1186:55-97. [DOI: 10.1007/978-3-030-28471-8_3] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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Hori J, Yamaguchi T, Keino H, Hamrah P, Maruyama K. Immune privilege in corneal transplantation. Prog Retin Eye Res 2019; 72:100758. [PMID: 31014973 DOI: 10.1016/j.preteyeres.2019.04.002] [Citation(s) in RCA: 92] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 04/14/2019] [Accepted: 04/16/2019] [Indexed: 12/13/2022]
Abstract
Corneal transplantation is the most successful solid organ transplantation performed in humans. The extraordinary success of orthotopic corneal allografts, in both humans and experimental animals, is related to the phenomenon of "immune privilege". Inflammation is self-regulated to preserve ocular functions because the eye has immune privilege. At present, three major mechanisms are considered to provide immune privilege in corneal transplantation: 1) anatomical, cellular, and molecular barriers in the cornea; 2) tolerance related to anterior chamber-associated immune deviation and regulatory T cells; and 3) an immunosuppressive intraocular microenvironment. This review describes the mechanisms of immune privilege that have been elucidated from animal models of ocular inflammation, especially those involving corneal transplantation, and its relevance for the clinic. An update on molecular, cellular, and neural interactions in local and systemic immune regulation is provided. Therapeutic strategies for restoring immune privilege are also discussed.
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Affiliation(s)
- Junko Hori
- Department of Ophthalmology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan; Department of Ophthalmology, Nippon Medical School, Tama-Nagayama Hospital, 1-7-1 Nagayama, Tama, Tokyo, 206-8512, Japan.
| | - Takefumi Yamaguchi
- Department of Ophthalmology, Tokyo Dental College Ichikawa General Hospital, 5-11-13 Sugano, Ichikawa-shi, Chiba, 272-8513, Japan; Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Hiroshi Keino
- Department of Ophthalmology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka-shi, Tokyo, 181-8611, Japan
| | - Pedram Hamrah
- Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Tufts University, 800 Washington St, Boston, MA, 02111, USA; Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Tufts University, 800 Washington St, Boston, MA, 02111, USA
| | - Kazuichi Maruyama
- Department of Innovative Visual Science, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
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Lee HS, Kwon JY, Joo CK. Comparative immunological study of penetrating and anterior lamellar keratoplasty in a murine model. Exp Eye Res 2018; 169:141-148. [PMID: 29305888 DOI: 10.1016/j.exer.2017.12.014] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Revised: 10/05/2017] [Accepted: 12/31/2017] [Indexed: 01/11/2023]
Abstract
In lamellar keratoplasty, the diseased part of a cornea is replaced while the healthy tissue remains lamellar keratoplasty has the advantage of better graft survival compared to penetrating keratoplasty (PK). We compared the immunological responses to PK and anterior lamellar keratoplasty (ALK) in a murine model. PK or ALK was performed using C57BL/6 donor grafts and BALB/c recipients, and graft opacity was assessed to evaluate graft rejection up to 8 weeks. We evaluated the immunological responses in both groups, which were not clinically considered as graft failure on postoperative day 21. PK mice showed reduced clinical graft survival compared to ALK mice. The mRNA expression of inflammatory mediators, such as IL-1β, IFN-γ, and granzyme B, in grafted corneas of PK mice, was significantly increased compared to the levels in ALK mice at postoperative day 21. PK led to a higher delayed-type hypersensitivity response and IFN-γ secretion in an in vitro T cell assay from draining lymph nodes (LNs), as compared to ALK. Furthermore, PK showed increased angiogenesis and lymphangiogenesis in grafted corneas compared to ALK and led to greater infiltration of CD3+ T cells into grafted corneas and increased frequencies of mature antigen presenting cells (APC; MHC-IIhighCD11c + cells) and IL-12 + dendritic cells (DCs) in the draining LNs of transplanted mice. In conclusion, PK results in increased graft rejection compared to ALK through relatively increased neovascularization and lymphangiogenesis, which can induce infiltration of pathologic T cells and mature APC migration into grafted corneas and draining LNs.
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Affiliation(s)
- Hyun Soo Lee
- Department of Ophthalmology, St. Paul's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; Catholic Institute for Visual Science, Seoul St. Mary's Hospital, Seoul, Republic of Korea
| | - Ji Young Kwon
- Catholic Institute for Visual Science, Seoul St. Mary's Hospital, Seoul, Republic of Korea
| | - Choun-Ki Joo
- Catholic Institute for Visual Science, Seoul St. Mary's Hospital, Seoul, Republic of Korea.
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Santos-Ferreira TF, Borsch O, Ader M. Rebuilding the Missing Part-A Review on Photoreceptor Transplantation. Front Syst Neurosci 2017; 10:105. [PMID: 28105007 PMCID: PMC5214672 DOI: 10.3389/fnsys.2016.00105] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Accepted: 12/12/2016] [Indexed: 01/13/2023] Open
Abstract
Vision represents one of the main senses for humans to interact with their environment. Our sight relies on the presence of fully functional light sensitive cells – rod and cone photoreceptors — allowing us to see under dim (rods) and bright (cones) light conditions. Photoreceptor degeneration is one of the major causes for vision impairment in industrialized countries and it is highly predominant in the population above the age of 50. Thus, with the continuous increase in life expectancy it will make retinal degeneration reach an epidemic proportion. To date, there is no cure established for photoreceptor loss, but several therapeutic approaches, spanning from neuroprotection, pharmacological drugs, gene therapy, retinal prosthesis, and cell (RPE or photoreceptor) transplantation, have been developed over the last decade with some already introduced in clinical trials. In this review, we focus on current developments in photoreceptor transplantation strategies, its major breakthroughs, current limitations and the next challenges to translate such cell-based approaches toward clinical application.
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Affiliation(s)
- Tiago F Santos-Ferreira
- DFG-Center for Regenerative Therapies Dresden, Cluster of Excellence, Technische Universität Dresden Dresden, Germany
| | - Oliver Borsch
- DFG-Center for Regenerative Therapies Dresden, Cluster of Excellence, Technische Universität Dresden Dresden, Germany
| | - Marius Ader
- DFG-Center for Regenerative Therapies Dresden, Cluster of Excellence, Technische Universität Dresden Dresden, Germany
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Yu T, Rajendran V, Griffith M, Forrester JV, Kuffová L. High-risk corneal allografts: A therapeutic challenge. World J Transplant 2016; 6:10-27. [PMID: 27011902 PMCID: PMC4801785 DOI: 10.5500/wjt.v6.i1.10] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Revised: 10/03/2015] [Accepted: 12/04/2015] [Indexed: 02/05/2023] Open
Abstract
Corneal transplantation is the most common surgical procedure amongst solid organ transplants with a high survival rate of 86% at 1-year post-grafting. This high success rate has been attributed to the immune privilege of the eye. However, mechanisms originally thought to promote immune privilege, such as the lack of antigen presenting cells and vessels in the cornea, are challenged by recent studies. Nevertheless, the immunological and physiological features of the cornea promoting a relatively weak alloimmune response is likely responsible for the high survival rate in “low-risk” settings. Furthermore, although corneal graft survival in “low-risk” recipients is favourable, the prognosis in “high-risk” recipients for corneal graft is poor. In “high-risk” grafts, the process of indirect allorecognition is accelerated by the enhanced innate and adaptive immune responses due to pre-existing inflammation and neovascularization of the host bed. This leads to the irreversible rejection of the allograft and ultimately graft failure. Many therapeutic measures are being tested in pre-clinical and clinical studies to counter the immunological challenge of “high-risk” recipients. Despite the prevailing dogma, recent data suggest that tissue matching together with use of systemic immunosuppression may increase the likelihood of graft acceptance in “high-risk” recipients. However, immunosuppressive drugs are accompanied with intolerance/side effects and toxicity, and therefore, novel cell-based therapies are in development which target host immune cells and restore immune homeostasis without significant side effect of treatment. In addition, developments in regenerative medicine may be able to solve both important short comings of allotransplantation: (1) graft rejection and ultimate graft failure; and (2) the lack of suitable donor corneas. The advances in technology and research indicate that wider therapeutic choices for patients may be available to address the worldwide problem of corneal blindness in both “low-risk” and “high-risk” hosts.
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Ouyang H, Goldberg JL, Chen S, Li W, Xu GT, Li W, Zhang K, Nussenblatt RB, Liu Y, Xie T, Chan CC, Zack DJ. Ocular Stem Cell Research from Basic Science to Clinical Application: A Report from Zhongshan Ophthalmic Center Ocular Stem Cell Symposium. Int J Mol Sci 2016; 17:415. [PMID: 27102165 PMCID: PMC4813266 DOI: 10.3390/ijms17030415] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2016] [Revised: 03/17/2016] [Accepted: 03/17/2016] [Indexed: 12/16/2022] Open
Abstract
Stem cells hold promise for treating a wide variety of diseases, including degenerative disorders of the eye. The eye is an ideal organ for stem cell therapy because of its relative immunological privilege, surgical accessibility, and its being a self-contained system. The eye also has many potential target diseases amenable to stem cell-based treatment, such as corneal limbal stem cell deficiency, glaucoma, age-related macular degeneration (AMD), and retinitis pigmentosa (RP). Among them, AMD and glaucoma are the two most common diseases, affecting over 200 million people worldwide. Recent results on the clinical trial of retinal pigment epithelial (RPE) cells from human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) in treating dry AMD and Stargardt’s disease in the US, Japan, England, and China have generated great excitement and hope. This marks the beginning of the ocular stem cell therapy era. The recent Zhongshan Ophthalmic Center Ocular Stem Cell Symposium discussed the potential applications of various stem cell types in stem cell-based therapies, drug discoveries and tissue engineering for treating ocular diseases.
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Affiliation(s)
- Hong Ouyang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
| | - Jeffrey L Goldberg
- Department of Ophthalmology, Stanford University, Palo Alto, CA 94303, USA.
| | - Shuyi Chen
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
| | - Wei Li
- Unit on Retinal Neurophysiology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
| | - Guo-Tong Xu
- Department of Ophthalmology, Tongji University, Shanghai 200092, China.
| | - Wei Li
- Department of Ophthalmology, Xiamen University, Xiamen 361005, China.
| | - Kang Zhang
- Department of Ophthalmology, University of California San Diego, San Diego, CA 92093, USA.
| | - Robert B Nussenblatt
- Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
| | - Yizhi Liu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
| | - Ting Xie
- Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
| | - Chi-Chao Chan
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
- Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
| | - Donald J Zack
- Wilmer Ophthalmological Institute, Johns Hopkins University, Baltimore, MD 21231, USA.
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de Andrade FA, Fiorot SHS, Benchimol EI, Provenzano J, Martins VJ, Levy RA. The autoimmune diseases of the eyes. Autoimmun Rev 2016; 15:258-71. [DOI: 10.1016/j.autrev.2015.12.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2015] [Accepted: 11/27/2015] [Indexed: 02/06/2023]
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12
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Schewitz-Bowers LP, Lee RWJ, Dick AD. Immune mechanisms of intraocular inflammation. EXPERT REVIEW OF OPHTHALMOLOGY 2014. [DOI: 10.1586/eop.09.68] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Schmidt-Christensen A, Hansen L, Ilegems E, Fransén-Pettersson N, Dahl U, Gupta S, Larefalk A, Hannibal TD, Schulz A, Berggren PO, Holmberg D. Imaging dynamics of CD11c⁺ cells and Foxp3⁺ cells in progressive autoimmune insulitis in the NOD mouse model of type 1 diabetes. Diabetologia 2013; 56:2669-78. [PMID: 23963325 DOI: 10.1007/s00125-013-3024-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2013] [Accepted: 07/17/2013] [Indexed: 02/02/2023]
Abstract
AIMS/HYPOTHESIS The aim of this study was to visualise the dynamics and interactions of the cells involved in autoimmune-driven inflammation in type 1 diabetes. METHODS We adopted the anterior chamber of the eye (ACE) transplantation model to perform non-invasive imaging of leucocytes infiltrating the endocrine pancreas during initiation and progression of insulitis in the NOD mouse. Individual, ACE-transplanted islets of Langerhans were longitudinally and repetitively imaged by stereomicroscopy and two-photon microscopy to follow fluorescently labelled leucocyte subsets. RESULTS We demonstrate that, in spite of the immune privileged status of the eye, the ACE-transplanted islets develop infiltration and beta cell destruction, recapitulating the autoimmune insulitis of the pancreas, and exemplify this by analysing reporter cell populations expressing green fluorescent protein under the Cd11c or Foxp3 promoters. We also provide evidence that differences in morphological appearance of subpopulations of infiltrating leucocytes can be correlated to their distinct dynamic behaviour. CONCLUSIONS/INTERPRETATION Together, these findings demonstrate that the kinetics and dynamics of these key cellular components of autoimmune diabetes can be elucidated using this imaging platform for single cell resolution, non-invasive and repetitive monitoring of the individual islets of Langerhans during the natural development of autoimmune diabetes.
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Affiliation(s)
- Anja Schmidt-Christensen
- ISIM-Immunology, Faculty of Health and Medical Sciences, Copenhagen University, Copenhagen, Denmark
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Settimio R, Clara DF, Franca F, Francesca S, Michele D. Resolvin D1 reduces the immunoinflammatory response of the rat eye following uveitis. Mediators Inflamm 2012; 2012:318621. [PMID: 23304060 PMCID: PMC3529870 DOI: 10.1155/2012/318621] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2012] [Revised: 11/14/2012] [Accepted: 11/14/2012] [Indexed: 12/30/2022] Open
Abstract
This study investigated whether the administration of resolvin D1 to rats with endotoxininduced uveitis (EIU) ameliorates the immuno-inflammatory profile of the eye. 24 h after the administration of 200 μg LPS into the footpad of Sprague-Dawley rats, severe changes of the structure of the eye occurred concomitantly with a severe inflammatory and immune response. These latter included strong infiltration of PMN leukocytes CD11b(+) T-lymphocytes CD4(+) and CD8(+) within the eye and a significant release of the cytokines/chemokines TNF-alpha, CXCL8, and RANTES too. Bolus of resolvin D1 (RvD1; 10-100-1000 ng/kg in 200 μL of sterile saline via the tail vein) significantly and dose-dependently (i) reduced the development of the ocular derangement caused by LPS; (ii) reduced the clinical score attributed to EIU; (iii) reduced the protein concentration and myeloperoxidase activity (MPO) in aqueous humor (AqH); and (iv) reduced neutrophils, T-lymphocytes, and cytokines within the eye.
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Affiliation(s)
- Rossi Settimio
- Department of Ophthalmology, Second University of Naples, 80100 Naples, Italy
| | - Di Filippo Clara
- Department of Experimental Medicine, Section of Pharmacology “L. Donatelli”, Second University of Naples, Via Costantinopoli 16, 80138 Naples, Italy
| | - Ferraraccio Franca
- Department of Clinical, Public and Preventive Medicine, Second University of Naples, 80138 Naples, Italy
| | - Simonelli Francesca
- Department of Ophthalmology, Second University of Naples, 80100 Naples, Italy
| | - D'Amico Michele
- Department of Experimental Medicine, Section of Pharmacology “L. Donatelli”, Second University of Naples, Via Costantinopoli 16, 80138 Naples, Italy
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Mochizuki M, Sugita S, Kamoi K. Immunological homeostasis of the eye. Prog Retin Eye Res 2012; 33:10-27. [PMID: 23108335 DOI: 10.1016/j.preteyeres.2012.10.002] [Citation(s) in RCA: 111] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2012] [Revised: 10/05/2012] [Accepted: 10/05/2012] [Indexed: 12/22/2022]
Abstract
Uveitis is a sight-threatening disease caused by autoimmune or infection-related immune responses. Studies in experimental autoimmune uveitis and in human diseases imply that activated CD4(+) T cells, Th1 and Th17 cells, play an effector role in ocular inflammation. The eye has a unique regional immune system to protect vision-related cells and tissues from these effector T cells. The immunological balance between the pathogenic CD4(+) T cells and regional immune system in the eye contributes to the maintenance of ocular homeostasis and good vision. Current studies have demonstrated that ocular parenchymal cells at the inner surface of the blood-ocular barrier, i.e. corneal endothelial (CE) cells, iris pigment epithelial (PE) cells, ciliary body PE cells, and retinal PE cells, contribute to the regional immune system of the eye. Murine ocular resident cells directly suppress activation of bystander T cells and production of inflammatory cytokines. The ocular resident cells possess distinct properties of immunoregulation that are related to disparate anatomical location. CE cells and iris PE cells, which are located at the anterior segment of the eye and face the aqueous humor, suppress activation of T cells via cell-to-cell contact mechanisms, whereas retinal PE cells suppress the activation of T cells via soluble factors. In addition to direct immune suppression, the ocular resident cells have another unique immunosuppressive property, the induction of CD25(+)Foxp3(+) Treg cells that also suppress the activation of bystander T cells. Iris PE cells convert CD8(+) T cells into Treg cells, while retinal PE cells convert CD4(+) T cells greatly and CD8(+) T cells moderately into Treg cells. CE cells also convert both CD4(+) T cells and CD8(+) T cells into Treg cells. The immunomodulation by ocular resident cells is mediated by various soluble or membrane-bound molecules that include TGF-β TSP-1, B7-2 (CD86), CTLA-2α, PD-L1 (B7-H1), galectin 1, pigment epithelial-derived factor PEDF), GIRTL, and retinoic acid. Human retinal PE cells also possess similar immune properties to induce Treg cells. Although there are many issues to be answered, human Treg cells induced by ocular resident cells such as retinal PE cells and related immunosuppressive molecules can be applied as immune therapy for refractive autoimmune uveitis in humans in the future.
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Affiliation(s)
- Manabu Mochizuki
- Department of Ophthalmology & Visual Science, Tokyo Medical and Dental University, 1-5-45 Yushima, Tokyo 113-8519, Japan.
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Zhou R, Horai R, Silver PB, Mattapallil MJ, Zárate-Bladés CR, Chong WP, Chen J, Rigden RC, Villasmil R, Caspi RR. The living eye "disarms" uncommitted autoreactive T cells by converting them to Foxp3(+) regulatory cells following local antigen recognition. THE JOURNAL OF IMMUNOLOGY 2012; 188:1742-50. [PMID: 22238462 DOI: 10.4049/jimmunol.1102415] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Immune privilege is used by the eye, brain, reproductive organs, and gut to preserve structural and functional integrity in the face of inflammation. The eye is arguably the most vulnerable and, therefore, also the most "privileged" of tissues; paradoxically, it remains subject to destructive autoimmunity. It has been proposed, although never proven in vivo, that the eye can induce T regulatory cells (Tregs) locally. Using Foxp3-GFP reporter mice expressing a retina-specific TCR, we now show that uncommitted T cells rapidly convert in the living eye to Foxp3(+) Tregs in a process involving retinal Ag recognition, de novo Foxp3 induction, and proliferation. This takes place within the ocular tissue and is supported by retinoic acid, which is normally present in the eye because of its function in the chemistry of vision. Nonconverted T cells showed evidence of priming but appeared restricted from expressing effector function in the eye. Pre-existing ocular inflammation impeded conversion of uncommitted T cells into Tregs. Importantly, retina-specific T cells primed in vivo before introduction into the eye were resistant to Treg conversion in the ocular environment and, instead, caused severe uveitis. Thus, uncommitted T cells can be disarmed, but immune privilege is unable to protect from uveitogenic T cells that have acquired effector function prior to entering the eye. These findings shed new light on the phenomenon of immune privilege and on its role, as well as its limitations, in actively controlling immune responses in the tissue.
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Affiliation(s)
- Ru Zhou
- Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892-1857, USA
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Dick AD. Road to Fulfilment: Taming the Immune Response to Restore Vision. Ophthalmic Res 2012; 48:43-9. [DOI: 10.1159/000335982] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2011] [Accepted: 11/30/2011] [Indexed: 12/14/2022]
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The mechanisms and consequences of ultraviolet-induced immunosuppression in the skin and eye. Eye Contact Lens 2011; 37:176-84. [PMID: 21709488 DOI: 10.1097/icl.0b013e31821d7573] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Ultraviolet radiation (UVR) of the skin results in immune suppression to antigens encountered shortly after the exposure. The pathways leading to the downregulation in immunity are complex, initiated by chromophores located at the surface of the skin and ending with the generation of immunosuppressive mediators and regulatory cells. Ultraviolet-induced immunosuppression can be considered not only as beneficial, such as in preventing chronic inflammatory responses and allergic and automimmune reactions, but it can also be detrimental, such as in the lack of control of skin tumors and infectious diseases. The eye is an immune privileged site through a wide variety of mechanisms that allow selected immune responses without causing inflammation. The role of UVR in altering immune responses in the eye is not clear and is discussed in relation to photokeratitis, herpetic stromal keratitis, and pterygium.
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T cell responses in experimental viral retinitis: Mechanisms, peculiarities and implications for gene therapy with viral vectors. Prog Retin Eye Res 2011; 30:275-84. [DOI: 10.1016/j.preteyeres.2011.04.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2010] [Revised: 04/17/2011] [Accepted: 04/18/2011] [Indexed: 11/20/2022]
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Tezel G. The immune response in glaucoma: a perspective on the roles of oxidative stress. Exp Eye Res 2010; 93:178-86. [PMID: 20709058 DOI: 10.1016/j.exer.2010.07.009] [Citation(s) in RCA: 107] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2009] [Revised: 07/14/2010] [Accepted: 07/15/2010] [Indexed: 11/26/2022]
Abstract
Neurodegenerative insults and glial activation during glaucomatous neurodegeneration initiate an immune response to restore tissue homeostasis and facilitate tissue cleaning and healing. However, increasing risk factors over a chronic and cumulative period may lead to a failure in the regulation of innate and adaptive immune response pathways and represent a route for conversion of the beneficial immunity into a neuroinflammatory degenerative process contributing to disease progression. Oxidative stress developing through the pathogenic cellular processes of glaucoma, along with the aging-related component of oxidative stress, likely plays a critical role in shifting the physiological equilibrium. This review aims to provide a perspective on the complex interplay of cellular events during glaucomatous neurodegeneration by proposing a unifying scheme that integrates oxidative stress-related risk factors with the altered regulation of immune response in glaucoma.
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Affiliation(s)
- Gülgün Tezel
- Department of Ophthalmology & Visual Sciences, University of Louisville, Louisville, KY, USA.
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