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1
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Yang SN, Shi Y, Berggren PO. The anterior chamber of the eye technology and its anatomical, optical, and immunological bases. Physiol Rev 2024; 104:881-929. [PMID: 38206586 PMCID: PMC11381035 DOI: 10.1152/physrev.00024.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 11/30/2023] [Accepted: 01/05/2024] [Indexed: 01/12/2024] Open
Abstract
The anterior chamber of the eye (ACE) is distinct in its anatomy, optics, and immunology. This guarantees that the eye perceives visual information in the context of physiology even when encountering adverse incidents like inflammation. In addition, this endows the ACE with the special nursery bed iris enriched in vasculatures and nerves. The ACE constitutes a confined space enclosing an oxygen/nutrient-rich, immune-privileged, and less stressful milieu as well as an optically transparent medium. Therefore, aside from visual perception, the ACE unexpectedly serves as an excellent transplantation site for different body parts and a unique platform for noninvasive, longitudinal, and intravital microimaging of different grafts. On the basis of these merits, the ACE technology has evolved from the prototypical through the conventional to the advanced version. Studies using this technology as a versatile biomedical research platform have led to a diverse range of basic knowledge and in-depth understanding of a variety of cells, tissues, and organs as well as artificial biomaterials, pharmaceuticals, and abiotic substances. Remarkably, the technology turns in vivo dynamic imaging of the morphological characteristics, organotypic features, developmental fates, and specific functions of intracameral grafts into reality under physiological and pathological conditions. Here we review the anatomical, optical, and immunological bases as well as technical details of the ACE technology. Moreover, we discuss major achievements obtained and potential prospective avenues for this technology.
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Affiliation(s)
- Shao-Nian Yang
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden
| | - Yue Shi
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden
| | - Per-Olof Berggren
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden
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2
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Abu-Romman A, Scholand KK, Pal-Ghosh S, Yu Z, Kelagere Y, Yazdanpanah G, Kao WWY, Coulson-Thomas VJ, Stepp MA, de Paiva CS. Conditional deletion of CD25 in the corneal epithelium reveals sex differences in barrier disruption. Ocul Surf 2023; 30:57-72. [PMID: 37516317 PMCID: PMC10812880 DOI: 10.1016/j.jtos.2023.07.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 07/06/2023] [Accepted: 07/25/2023] [Indexed: 07/31/2023]
Abstract
PURPOSE IL-2 promotes activation, clonal expansion, and deletion of T cells. IL-2 signals through its heterotrimeric receptor (IL-2R) consisting of the CD25, CD122 and CD132 chains. CD25 knockout (KO) mice develop Sjögren Syndrome-like disease. This study investigates whether corneal CD25/IL-2 signaling is critical for ocular health. METHODS Eyes from C57BL/6 mice were collected and prepared for immunostaining or in-situ hybridization. Bulk RNA sequencing was performed on the corneal epithelium from wild-type and CD25KO mice. We generated a conditional corneal-specific deletion of CD25 in the corneal epithelium (CD25Δ/ΔCEpi). Corneal barrier function was evaluated based on the uptake of a fluorescent dye. Mice were subjected to unilateral corneal debridement, followed by epithelial closure over time. RESULTS In C57BL/6 mice, CD25 mRNA was expressed in ocular tissues. Protein expression of CD25, CD122, and CD132 was confirmed in the corneal epithelium. Delayed corneal re-epithelization was seen in female but not male CD25KO mice. There were 771 differentially expressed genes in the corneal epithelium of CD25KO compared to wild-type mice. While barrier function is disrupted in CD25Δ/ΔCEpi mice, re-epithelialization rates are not delayed. CONCLUSIONS All three chains of the IL-2R are expressed in the corneal epithelium. Our results indicate for the first time, deleting CD25 systemically in all tissues in the mouse and deleting CD25 locally in just the corneal epithelium compromises corneal epithelial barrier function, leading to dry eye disease in female mice. Future studies are needed to delineate the pathways used by IL-2 signaling to influence cornea homeostasis.
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Affiliation(s)
- Anmar Abu-Romman
- Ocular Surface Center, Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine, Houston, TX, United States.
| | - Kaitlin K Scholand
- Ocular Surface Center, Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine, Houston, TX, United States; Department of Biosciences, Rice University, Houston, TX, United States.
| | - Sonali Pal-Ghosh
- Department of Anatomy and Cell Biology, The George Washington University School of Medicine and Health Sciences, Washington, DC, United States.
| | - Zhiyuan Yu
- Ocular Surface Center, Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine, Houston, TX, United States.
| | - Yashaswini Kelagere
- Ocular Surface Center, Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine, Houston, TX, United States.
| | - Ghasem Yazdanpanah
- Ocular Surface Center, Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine, Houston, TX, United States.
| | - Winston W-Y Kao
- Department of Ophthalmology, University of Cincinnati, Cincinnati, OH, United States.
| | | | - Mary Ann Stepp
- Department of Anatomy and Cell Biology, The George Washington University School of Medicine and Health Sciences, Washington, DC, United States; Department of Ophthalmology, The George Washington University School of Medicine and Health Sciences, Washington, DC, United States.
| | - Cintia S de Paiva
- Ocular Surface Center, Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine, Houston, TX, United States; Department of Biosciences, Rice University, Houston, TX, United States.
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3
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Buonfiglio F, Pfeiffer N, Gericke A. Immunomodulatory and Antioxidant Drugs in Glaucoma Treatment. Pharmaceuticals (Basel) 2023; 16:1193. [PMID: 37765001 PMCID: PMC10535738 DOI: 10.3390/ph16091193] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 08/02/2023] [Accepted: 08/18/2023] [Indexed: 09/29/2023] Open
Abstract
Glaucoma, a group of diseases characterized by progressive retinal ganglion cell loss, cupping of the optic disc, and a typical pattern of visual field defects, is a leading cause of severe visual impairment and blindness worldwide. Elevated intraocular pressure (IOP) is the leading risk factor for glaucoma development. However, glaucoma can also develop at normal pressure levels. An increased susceptibility of retinal ganglion cells to IOP, systemic vascular dysregulation, endothelial dysfunction, and autoimmune imbalances have been suggested as playing a role in the pathophysiology of normal-tension glaucoma. Since inflammation and oxidative stress play a role in all forms of glaucoma, the goal of this review article is to present an overview of the inflammatory and pro-oxidant mechanisms in the pathophysiology of glaucoma and to discuss immunomodulatory and antioxidant treatment approaches.
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Affiliation(s)
- Francesco Buonfiglio
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany;
| | | | - Adrian Gericke
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany;
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4
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Santos LS, Rossi DA, Braz RF, Fonseca BB, Guidotti–Takeuchi M, Alves RN, Beletti ME, Almeida-Souza HO, Maia LP, Santos PDS, de Souza JB, de Melo RT. Roles of viable but non-culturable state in the survival of Campylobacter jejuni. Front Cell Infect Microbiol 2023; 13:1122450. [PMID: 37056707 PMCID: PMC10086134 DOI: 10.3389/fcimb.2023.1122450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 03/09/2023] [Indexed: 03/30/2023] Open
Abstract
Despite being considered fragile and fastidious, Campylobacter jejuni is the most prevalent cause of foodborne bacterial gastroenteritis, and chicken meat is considered the main vehicle of transmission to humans. This agent can survive adverse conditions in the form of biofilms, but extreme stress (nutritional, oxidative and thermal) promotes the acquisition of a state called viable but not culturable (VBNC). The emergence of this pathogen worldwide and the recent international requirements in its control instigated us to qualitatively and quantitatively estimate the time required for the acquisition of the VBNC form in 27 strains of C. jejuni, characterize morphological aspects, determine its adaptive and invasive potential and perform comparative metabolomic evaluation. Extreme stress promoted the complete acquisition of the VBNC form in a mean time of 26 days. Starting from an average initial count of 7.8 log CFU/mL, the first four days determined the greatest average reduction of the culturable form of 3.2 log CFU/mL. The scanning and transmission image analyses showed a transition from the typical viable form (VT) to the VBNC form, with initial acquisition of the straight rod shape, followed by loss of the flagella and subdivision into two to 11 imperfect cocci arranged in a chain and rich in cellular content, until their individual release. RT-PCR identified the presence of ciaB and p19 transcripts in the 27 cultivable C. jejuni strains, a character maintained in the VBNC form only for p19 and in 59.3% (16/27) of the VBNC strains for the ciaB gene. The average inoculation of 1.8 log CFU/mL of C. jejuni VBNC into primary chicken embryo hepatocyte cells promoted the occurrence of apoptosis processes significantly after 24 hours of contact by one of the strains tested. In C. jejuni VBNC, we detected higher expression of metabolites linked to protective and adaptation mechanisms and of volatile organic precursor compounds indicative of metabolism interruption. The oscillations in the time of acquisition of the VBNC form together with the presence of transcripts for ciaB and p19, the identification of cell lysis and metabolites that ensure the maintenance of the pathogen alert to the fact that C. jejuni VBNC remains virulent and adapted to stress, which makes evident the potential danger of this latent form, which is not detectable by official methodologies.
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Affiliation(s)
- Leticia Silva Santos
- Laboratory of Molecular Epidemiology, Federal University of Uberlandia, Uberlandia, Brazil
| | - Daise Aparecida Rossi
- Laboratory of Molecular Epidemiology, Federal University of Uberlandia, Uberlandia, Brazil
| | | | | | | | | | | | | | - Larissa Prado Maia
- Biotechnology Institute, Federal University of Uberlandia, Uberlandia, Brazil
| | | | | | - Roberta Torres de Melo
- Laboratory of Molecular Epidemiology, Federal University of Uberlandia, Uberlandia, Brazil
- *Correspondence: Roberta Torres de Melo,
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5
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Du Y, Yan B. Ocular immune privilege and retinal pigment epithelial cells. J Leukoc Biol 2023; 113:288-304. [PMID: 36805720 DOI: 10.1093/jleuko/qiac016] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Indexed: 02/04/2023] Open
Abstract
The ocular tissue microenvironment is immune-privileged and uses multiple immunosuppressive mechanisms to prevent the induction of inflammation. The retinal pigment epithelium plays an essential role in ocular immune privilege. In addition to serving as a blood barrier separating the fenestrated choriocapillaris from the retina, the retinal pigment epithelium is a source of immunosuppressive cytokines and membrane-bound negative regulators that modulate the activity of immune cells within the retina. This article reviews the current understanding of how retinal pigment epithelium cells mediate immune regulation, focusing on the changes under pathologic conditions.
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Affiliation(s)
- Yuxiang Du
- Institute of Precision Medicine, Jining Medical University, No. 133, Hehua Road, Taibaihu New District, Jining, Shandong 272067, People's Republic of China
| | - Bo Yan
- Institute of Precision Medicine, Jining Medical University, No. 133, Hehua Road, Taibaihu New District, Jining, Shandong 272067, People's Republic of China
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6
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Akama-Garren EH, Miller P, Carroll TM, Tellier M, Sutendra G, Buti L, Zaborowska J, Goldin RD, Slee E, Szele FG, Murphy S, Lu X. Regulation of immunological tolerance by the p53-inhibitor iASPP. Cell Death Dis 2023; 14:84. [PMID: 36746936 PMCID: PMC9902554 DOI: 10.1038/s41419-023-05567-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 12/23/2022] [Accepted: 01/06/2023] [Indexed: 02/08/2023]
Abstract
Maintenance of immunological homeostasis between tolerance and autoimmunity is essential for the prevention of human diseases ranging from autoimmune disease to cancer. Accumulating evidence suggests that p53 can mitigate phagocytosis-induced adjuvanticity thereby promoting immunological tolerance following programmed cell death. Here we identify Inhibitor of Apoptosis Stimulating p53 Protein (iASPP), a negative regulator of p53 transcriptional activity, as a regulator of immunological tolerance. iASPP-deficiency promoted lung adenocarcinoma and pancreatic cancer tumorigenesis, while iASPP-deficient mice were less susceptible to autoimmune disease. Immune responses to iASPP-deficient tumors exhibited hallmarks of immunosuppression, including activated regulatory T cells and exhausted CD8+ T cells. Interestingly, iASPP-deficient tumor cells and tumor-infiltrating myeloid cells, CD4+, and γδ T cells expressed elevated levels of PD-1H, a recently identified transcriptional target of p53 that promotes tolerogenic phagocytosis. Identification of an iASPP/p53 axis of immune homeostasis provides a therapeutic opportunity for both autoimmune disease and cancer.
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Affiliation(s)
- Elliot H Akama-Garren
- Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7DQ, UK.
- Harvard-MIT Health Sciences and Technology, Harvard Medical School, Boston, MA, 02115, USA.
| | - Paul Miller
- Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7DQ, UK
| | - Thomas M Carroll
- Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7DQ, UK
| | - Michael Tellier
- Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, UK
| | - Gopinath Sutendra
- Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7DQ, UK
- Department of Medicine, University of Alberta, Edmonton, AB, T6G 2B7, Canada
| | - Ludovico Buti
- Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7DQ, UK
- Charles River Laboratories, Leiden, Netherlands
| | - Justyna Zaborowska
- Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, UK
| | - Robert D Goldin
- Centre for Pathology, St. Mary's Hospital, Imperial College, London, W2 1NY, UK
| | - Elizabeth Slee
- Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7DQ, UK
| | - Francis G Szele
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, UK
| | - Shona Murphy
- Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, UK
| | - Xin Lu
- Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7DQ, UK.
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7
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Zhang R, Song Y, Su X. Necroptosis and Alzheimer's Disease: Pathogenic Mechanisms and Therapeutic Opportunities. J Alzheimers Dis 2023; 94:S367-S386. [PMID: 36463451 PMCID: PMC10473100 DOI: 10.3233/jad-220809] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/07/2022] [Indexed: 11/30/2022]
Abstract
Alzheimer's disease (AD) is considered to be the most common neurodegenerative disease, with clinical symptoms encompassing progressive memory loss and cognitive impairment. Necroptosis is a form of programmed necrosis that promotes cell death and neuroinflammation, which further mediates the pathogenesis of several neurodegenerative diseases, especially AD. Current evidence has strongly suggested that necroptosis is activated in AD brains, resulting in neuronal death and cognitive impairment. We searched the PubMed database, screening all articles published before September 28, 2022 related to necroptosis in the context of AD pathology. The keywords in the search included: "necroptosis", "Alzheimer's disease", "signaling pathways", "Aβ", Aβo", "Tau", "p-Tau", "neuronal death", "BBB damage", "neuroinflammation", "microglia", "mitochondrial dysfunction", "granulovacuolar degeneration", "synaptic loss", "axonal degeneration", "Nec-1", "Nec-1s", "GSK872", "NSA", "OGA", "RIPK1", "RIPK3", and "MLKL". Results show that necroptosis has been involved in multiple pathological processes of AD, including amyloid-β aggregation, Tau accumulation, neuronal death, and blood-brain barrier damage, etc. More importantly, existing research on AD necroptosis interventions, including drug intervention and potential gene targets, as well as its current clinical development status, was discussed. Finally, the issues pertaining to necroptosis in AD were presented. Accordingly, this review may provide further insight into clinical perspectives and challenges for the future treatment of AD by targeting the necroptosis pathway.
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Affiliation(s)
- Ruxin Zhang
- Linfen People’s Hospital, Linfen, Shanxi, China
| | | | - Xuefeng Su
- Linfen People’s Hospital, Linfen, Shanxi, China
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8
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Mucosal immunology of the ocular surface. Mucosal Immunol 2022; 15:1143-1157. [PMID: 36002743 PMCID: PMC9400566 DOI: 10.1038/s41385-022-00551-6] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 05/26/2022] [Accepted: 06/10/2022] [Indexed: 02/04/2023]
Abstract
The eye is a sensory organ exposed to the environment and protected by a mucosal tissue barrier. While it shares a number of features with other mucosal tissues, the ocular mucosal system, composed of the conjunctiva, Meibomian glands, and lacrimal glands, is specialized to address the unique needs of (a) lubrication and (b) host defense of the ocular surface. Not surprisingly, most challenges, physical and immunological, to the homeostasis of the eye fall into those two categories. Dry eye, a dysfunction of the lacrimal glands and/or Meibomian glands, which can both cause, or arise from, sensory defects, including those caused by corneal herpes virus infection, serve as examples of these perturbations and will be discussed ahead. To preserve vision, dense neuronal and immune networks sense various stimuli and orchestrate responses, which must be tightly controlled to provide protection, while simultaneously minimizing collateral damage. All this happens against the backdrop of, and can be modified by, the microorganisms that colonize the ocular mucosa long term, or that are simply transient passengers introduced from the environment. This review will attempt to synthesize the existing knowledge and develop trends in the study of the unique mucosal and immune elements of the ocular surface.
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9
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Varin J, Morival C, Maillard N, Adjali O, Cronin T. Risk Mitigation of Immunogenicity: A Key to Personalized Retinal Gene Therapy. Int J Mol Sci 2021; 22:12818. [PMID: 34884622 PMCID: PMC8658027 DOI: 10.3390/ijms222312818] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 11/17/2021] [Accepted: 11/23/2021] [Indexed: 12/27/2022] Open
Abstract
Gene therapy (GT) for ocular disorders has advanced the most among adeno-associated virus (AAV)-mediated therapies, with one product already approved in the market. The bank of retinal gene mutations carefully compiled over 30 years, the small retinal surface that does not require high clinical vector stocks, and the relatively immune-privileged environment of the eye explain such success. However, adverse effects due to AAV-delivery, though rare in the retina have led to the interruption of clinical trials. Risk mitigation, as the key to safe and efficient GT, has become the focus of 'bedside-back-to-bench' studies. Herein, we overview the inflammatory adverse events described in retinal GT trials and analyze which components of the retinal immunological environment might be the most involved in these immune responses, with a focus on the innate immune system composed of microglial surveillance. We consider the factors that can influence inflammation in the retina after GT such as viral sensors in the retinal tissue and CpG content in promoters or transgene sequences. Finally, we consider options to reduce the immunological risk, including dose, modified capsids or exclusion criteria for clinical trials. A better understanding and mitigation of immune risk factors inducing host immunity in AAV-mediated retinal GT is the key to achieving safe and efficient GT.
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Affiliation(s)
| | | | | | - Oumeya Adjali
- CHU de Nantes, INSERM UMR1089, Translational Gene Therapy for Genetic Diseases, Université de Nantes, F-44200 Nantes, France; (J.V.); (C.M.); (N.M.)
| | - Therese Cronin
- CHU de Nantes, INSERM UMR1089, Translational Gene Therapy for Genetic Diseases, Université de Nantes, F-44200 Nantes, France; (J.V.); (C.M.); (N.M.)
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10
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Gregory-Ksander M, Marshak-Rothstein A. The FasLane to ocular pathology-metalloproteinase cleavage of membrane-bound FasL determines FasL function. J Leukoc Biol 2021; 110:965-977. [PMID: 33565149 DOI: 10.1002/jlb.3ri1220-834r] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 01/15/2021] [Accepted: 01/18/2021] [Indexed: 12/26/2022] Open
Abstract
Fas ligand (FasL) is best known for its ability to induce cell death in a wide range of Fas-expressing targets and to limit inflammation in immunoprivileged sites such as the eye. In addition, the ability of FasL to induce a much more extensive list of outcomes is being increasingly explored and accepted. These outcomes include the induction of proinflammatory cytokine production, T cell activation, and cell motility. However, the distinct and opposing functions of membrane-associated FasL (mFasL) and the C-terminal soluble FasL fragment (sFasL) released by metalloproteinase cleavage is less well documented and understood. Both mFasL and sFasL can form trimers that engage the trimeric Fas receptor, but only mFasL can form a multimeric complex in lipid rafts to trigger apoptosis and inflammation. By contrast, a number of reports have now documented the anti-apoptotic and anti-inflammatory activity of sFasL, pointing to a critical regulatory function of the soluble molecule. The immunomodulatory activity of FasL is particularly evident in ocular pathology where elimination of the metalloproteinase cleavage site and the ensuing increased expression of mFasL can severely exacerbate the extent of inflammation and cell death. By contrast, both homeostatic and increased expression of sFasL can limit inflammation and cell death. The mechanism(s) responsible for the protective activity of sFasL are discussed but remain controversial. Nevertheless, it will be important to consider therapeutic applications of sFasL for the treatment of ocular diseases such as glaucoma.
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Affiliation(s)
- Meredith Gregory-Ksander
- Schepens Eye Research Institute of Mass Eye and Ear, Harvard Medical School, Boston, Massachusetts, USA
| | - Ann Marshak-Rothstein
- Department of Medicine/Rheumatology, University of Massachusetts Medical School, Worcester, Massachusetts, USA
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11
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Castellarin M, Sands C, Da T, Scholler J, Graham K, Buza E, Fraietta JA, Zhao Y, June CH. A rational mouse model to detect on-target, off-tumor CAR T cell toxicity. JCI Insight 2020; 5:136012. [PMID: 32544101 PMCID: PMC7453898 DOI: 10.1172/jci.insight.136012] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 06/10/2020] [Indexed: 02/06/2023] Open
Abstract
Off-tumor targeting of human antigens is difficult to predict in preclinical animal studies and can lead to serious adverse effects in patients. To address this, we developed a mouse model with stable and tunable human Her2 (hHer2) expression on normal hepatic tissue and compared toxicity between affinity-tuned Her2 chimeric antigen receptor T cells (CARTs). In mice with hHer2-high livers, both the high-affinity (HA) and low-affinity (LA) CARTs caused lethal liver damage due to immunotoxicity. In mice with hHer2-low livers, LA-CARTs exhibited less liver damage and lower systemic levels of IFN-γ than HA-CARTs. We then compared affinity-tuned CARTs for their ability to control a hHer2-positive tumor xenograft in our model. Surprisingly, the LA-CARTs outperformed the HA-CARTs with superior antitumor efficacy in vivo. We hypothesized that this was due, in part, to T cell trafficking differences between LA and HA-CARTs and found that the LA-CARTs migrated out of the liver and infiltrated the tumor sooner than the HA-CARTs. These findings highlight the importance of T cell targeting in reducing toxicity of normal tissue and also in preventing off-tumor sequestration of CARTs, which reduces their therapeutic potency. Our model may be useful to evaluate various CARTs that have conditional expression of more than 1 single-chain variable fragment (scFv).
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MESH Headings
- Animals
- Cell Line, Tumor
- Disease Models, Animal
- Gene Expression Regulation/drug effects
- Humans
- Immunotherapy, Adoptive/methods
- Interferon-gamma/genetics
- Liver/drug effects
- Liver/pathology
- Mice
- Receptor, ErbB-2/genetics
- Receptors, Antigen, T-Cell/genetics
- Receptors, Antigen, T-Cell/immunology
- Receptors, Chimeric Antigen/genetics
- Receptors, Chimeric Antigen/immunology
- Single-Chain Antibodies/immunology
- Single-Chain Antibodies/pharmacology
- T-Lymphocytes/immunology
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Mauro Castellarin
- Center for Cellular Immunotherapies, Abramson Cancer Center, and
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine
| | - Caroline Sands
- Center for Cellular Immunotherapies, Abramson Cancer Center, and
| | - Tong Da
- Center for Cellular Immunotherapies, Abramson Cancer Center, and
| | - John Scholler
- Center for Cellular Immunotherapies, Abramson Cancer Center, and
| | - Kathleen Graham
- Center for Cellular Immunotherapies, Abramson Cancer Center, and
| | - Elizabeth Buza
- Department of Pathobiology, School of Veterinary Medicine, and
| | - Joseph A. Fraietta
- Center for Cellular Immunotherapies, Abramson Cancer Center, and
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Yangbing Zhao
- Center for Cellular Immunotherapies, Abramson Cancer Center, and
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine
| | - Carl H. June
- Center for Cellular Immunotherapies, Abramson Cancer Center, and
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine
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12
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Aaes TL, Verschuere H, Kaczmarek A, Heyndrickx L, Wiernicki B, Delrue I, De Craene B, Taminau J, Delvaeye T, Bertrand MJM, Declercq W, Berx G, Krysko DV, Adjemian S, Vandenabeele P. Immunodominant AH1 Antigen-Deficient Necroptotic, but Not Apoptotic, Murine Cancer Cells Induce Antitumor Protection. THE JOURNAL OF IMMUNOLOGY 2020; 204:775-787. [DOI: 10.4049/jimmunol.1900072] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 12/11/2019] [Indexed: 11/19/2022]
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13
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Krishnan A, Kocab AJ, Zacks DN, Marshak-Rothstein A, Gregory-Ksander M. A small peptide antagonist of the Fas receptor inhibits neuroinflammation and prevents axon degeneration and retinal ganglion cell death in an inducible mouse model of glaucoma. J Neuroinflammation 2019; 16:184. [PMID: 31570110 PMCID: PMC6767653 DOI: 10.1186/s12974-019-1576-3] [Citation(s) in RCA: 102] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Accepted: 08/29/2019] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Glaucoma is a complex, multifactorial disease where apoptosis, microglia activation, and inflammation have been linked to the death of retinal ganglion cells (RGCs) and axon degeneration. We demonstrated previously that FasL-Fas signaling was required for axon degeneration and death of RGCs in chronic and inducible mouse models of glaucoma and that Fas activation triggered RGC apoptosis, glial activation, and inflammation. Here, we investigated whether targeting the Fas receptor with a small peptide antagonist, ONL1204, has anti-inflammatory and neuroprotective effects in a microbead-induced mouse model of glaucoma. METHODS Intracameral injection of microbeads was used to elevate intraocular pressure (IOP) in Fas-deficient (Faslpr) mice and WT C57BL/6J mice that received an intravitreal injection of the Fas inhibitor, ONL1204 (2 μg/1 μl) (or vehicle only), on day 0 or day 7 after microbead injection. The IOP was monitored by rebound tonometry, and at 28 days post-microbead injection, Brn3a-stained RGCs and paraphenylenediamine (PPD)-stained axons were analyzed. The effects of ONL1204 on retinal microglia activation and the expression of inflammatory genes were analyzed by immunostaining of retinal flatmounts and quantitative PCR (qPCR). RESULTS Rebound tonometry showed equivalent elevation of IOP in all groups of microbead-injected mice. At 28 days post-microbead injection, the RGC and axon counts from microbead-injected Faslpr mice were equivalent to saline-injected (no IOP elevation) controls. Treatment with ONL1204 also significantly reduced RGC death and loss of axons in microbead-injected WT mice when compared to vehicle-treated controls, even when administered after IOP elevation. Confocal analysis of Iba1-stained retinal flatmounts and qPCR demonstrated that ONL1204 also abrogated microglia activation and inhibited the induction of multiple genes implicated in glaucoma, including cytokines and chemokines (GFAP, Caspase-8, TNFα, IL-1β, IL-6, IL-18, MIP-1α, MIP-1β, MIP-2, MCPI, and IP10), components of the complement cascade (C3, C1Q), Toll-like receptor pathway (TLR4), and inflammasome pathway (NLRP3). CONCLUSIONS These results serve as proof-of-principal that the small peptide inhibitor of the Fas receptor, ONL1204, can provide robust neuroprotection in an inducible mouse model of glaucoma, even when administered after IOP elevation. Moreover, Fas signaling contributes to the pathogenesis of glaucoma through activation of both apoptotic and inflammatory pathways.
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Affiliation(s)
- Anitha Krishnan
- Department of Ophthalmology, The Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, 20 Staniford Street, Boston, MA, USA
| | | | - David N Zacks
- Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI, USA
| | - Ann Marshak-Rothstein
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA
| | - Meredith Gregory-Ksander
- Department of Ophthalmology, The Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, 20 Staniford Street, Boston, MA, USA.
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Dostert C, Grusdat M, Letellier E, Brenner D. The TNF Family of Ligands and Receptors: Communication Modules in the Immune System and Beyond. Physiol Rev 2019; 99:115-160. [DOI: 10.1152/physrev.00045.2017] [Citation(s) in RCA: 319] [Impact Index Per Article: 53.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The tumor necrosis factor (TNF) and TNF receptor (TNFR) superfamilies (TNFSF/TNFRSF) include 19 ligands and 29 receptors that play important roles in the modulation of cellular functions. The communication pathways mediated by TNFSF/TNFRSF are essential for numerous developmental, homeostatic, and stimulus-responsive processes in vivo. TNFSF/TNFRSF members regulate cellular differentiation, survival, and programmed death, but their most critical functions pertain to the immune system. Both innate and adaptive immune cells are controlled by TNFSF/TNFRSF members in a manner that is crucial for the coordination of various mechanisms driving either co-stimulation or co-inhibition of the immune response. Dysregulation of these same signaling pathways has been implicated in inflammatory and autoimmune diseases, highlighting the importance of their tight regulation. Investigation of the control of TNFSF/TNFRSF activities has led to the development of therapeutics with the potential to reduce chronic inflammation or promote anti-tumor immunity. The study of TNFSF/TNFRSF proteins has exploded over the last 30 yr, but there remains a need to better understand the fundamental mechanisms underlying the molecular pathways they mediate to design more effective anti-inflammatory and anti-cancer therapies.
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Affiliation(s)
- Catherine Dostert
- Department of Infection and Immunity, Experimental and Molecular Immunology, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg; Odense Research Center for Anaphylaxis, Department of Dermatology and Allergy Center, Odense University Hospital, University of Southern Denmark, Odense, Denmark; and Life Sciences Research Unit, Molecular Disease Mechanisms Group, University of Luxembourg, Belvaux, Luxembourg
| | - Melanie Grusdat
- Department of Infection and Immunity, Experimental and Molecular Immunology, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg; Odense Research Center for Anaphylaxis, Department of Dermatology and Allergy Center, Odense University Hospital, University of Southern Denmark, Odense, Denmark; and Life Sciences Research Unit, Molecular Disease Mechanisms Group, University of Luxembourg, Belvaux, Luxembourg
| | - Elisabeth Letellier
- Department of Infection and Immunity, Experimental and Molecular Immunology, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg; Odense Research Center for Anaphylaxis, Department of Dermatology and Allergy Center, Odense University Hospital, University of Southern Denmark, Odense, Denmark; and Life Sciences Research Unit, Molecular Disease Mechanisms Group, University of Luxembourg, Belvaux, Luxembourg
| | - Dirk Brenner
- Department of Infection and Immunity, Experimental and Molecular Immunology, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg; Odense Research Center for Anaphylaxis, Department of Dermatology and Allergy Center, Odense University Hospital, University of Southern Denmark, Odense, Denmark; and Life Sciences Research Unit, Molecular Disease Mechanisms Group, University of Luxembourg, Belvaux, Luxembourg
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15
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Heckmann BL, Tummers B, Green DR. Crashing the computer: apoptosis vs. necroptosis in neuroinflammation. Cell Death Differ 2018; 26:41-52. [PMID: 30341422 DOI: 10.1038/s41418-018-0195-3] [Citation(s) in RCA: 105] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Revised: 08/07/2018] [Accepted: 08/10/2018] [Indexed: 12/20/2022] Open
Abstract
Programmed cell death (PCD) plays critical roles in development, homeostasis, and both control and progression of a plethora of diseases, including cancer and neurodegenerative pathologies. Besides classical apoptosis, several different forms of PCD have now been recognized, including necroptosis. The way a cell dies determines the reaction of the surrounding environment, and immune activation in response to cell death proceeds in a manner dependent on which death pathways are activated. Apoptosis and necroptosis are major mechanisms of cell death that typically result in opposing immune responses. Apoptotic death usually leads to immunologically silent responses whereas necroptotic death releases molecules that promote inflammation, a process referred to as necroinflammation. Diseases of the nervous system, in particular neurodegenerative diseases, are characterized by neuronal death and progressive neuroinflammation. The mechanisms of neuronal death are not well defined and significant cross-talk between pathways has been suggested. Moreover, it has been proposed that the dying of neurons is a catalyst for activating immune cells in the brain and sustaining inflammatory output. In the current review we discuss the effects of apoptotis and necroptosis on inflammatory immune activation, and evaluate the roles of each cell death pathway in a variety of pathologies with specific focus on neurodegeneration. A putative model is proposed for the regulation of neuronal death and neuroinflammation that features a role for both the apoptotic and necroptotic pathways in disease establishment and progression.
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Affiliation(s)
- Bradlee L Heckmann
- Department of Immunology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Bart Tummers
- Department of Immunology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Douglas R Green
- Department of Immunology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
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16
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Zittoon RF, Madian YT, Alhennawi DEM, Nadeem HS. Cochlear Changes Caused by Peginterferon α-2b. J Interferon Cytokine Res 2018; 38:311-316. [PMID: 30016180 DOI: 10.1089/jir.2018.0012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
To evaluate the effect of peginterferon α-2b on guinea pigs' hearing and its cochlea, and to determine whether these effects are permanent or reversible. This study is an experimental animal study done on the organs of Corti of 30 guinea pigs after a peginterferon α-2b injection course. The cochleae of guinea pigs were extracted and examined by scanning electron microscopy for the right side and immunohistochemistry for the left side. All guinea pigs were subjected to pinna reflex, otological examination, and distortion product otoacoustic emission (DPOAE) both before and after the receiving of interferon (IFN). Electron microscopic scanning and immunohistochemistry of the cochleae revealed that peginterferon α-2b has a harmful effect on guinea pigs' cochleae, in the form of structural changes in the hair cells and supporting cells with apoptotic changes in the organ of Corti and the stria vascularis. These changes were reversible. DPOAE showed a significant reduction in distortion product mean amplitude and signal-to-noise ratio in all frequencies after 3 days from the last dose of IFN injection except at 1,006 Hz. After 14 days, there was a significant improvement in most of the frequencies, but are still below the normal values.
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Affiliation(s)
- Reham F Zittoon
- 1 Department of Otorhinolaryngology, Faculty of Medicine, Suez Canal University , Ismailia, Egypt
| | - Yasser T Madian
- 1 Department of Otorhinolaryngology, Faculty of Medicine, Suez Canal University , Ismailia, Egypt
| | - Diaa Eldeen M Alhennawi
- 1 Department of Otorhinolaryngology, Faculty of Medicine, Suez Canal University , Ismailia, Egypt
| | - Hany S Nadeem
- 2 Department of Anatomy, Faculty of Medicine, Ain Shams University , Cairo, Egypt
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17
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Girardot T, Rimmelé T, Venet F, Monneret G. Apoptosis-induced lymphopenia in sepsis and other severe injuries. Apoptosis 2018; 22:295-305. [PMID: 27812767 DOI: 10.1007/s10495-016-1325-3] [Citation(s) in RCA: 147] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Sepsis and other acute injuries such as severe trauma, extensive burns, or major surgeries, are usually followed by a period of marked immunosuppression. In particular, while lymphocytes play a pivotal role in immune response, their functions and numbers are profoundly altered after severe injuries. Apoptosis plays a central role in this process by affecting immune response at various levels. Indeed, apoptosis-induced lymphopenia duration and depth have been associated with higher risk of infection and mortality in various clinical settings. Therapies modulating apoptosis represent an interesting approach to restore immune competence after acute injury, although their use in clinical practice still presents several limitations. After briefly describing the apoptosis process in physiology and during severe injuries, we will explore the immunological consequences of injury-induced lymphocyte apoptosis, and describe associations with clinically relevant outcomes in patients. Therapeutic perspectives targeting apoptosis will also be discussed.
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Affiliation(s)
- Thibaut Girardot
- Anesthesia and Critical Care Medicine Department, Hospices Civils de Lyon, Edouard Herriot Hospital, Lyon, France.,EA 7426 Pathophysiology of Injury-Induced Immunosuppression (Université Claude Bernard Lyon 1-Hospices Civils de Lyon-bioMérieux), Edouard Herriot Hospital, Lyon, France
| | - Thomas Rimmelé
- Anesthesia and Critical Care Medicine Department, Hospices Civils de Lyon, Edouard Herriot Hospital, Lyon, France.,EA 7426 Pathophysiology of Injury-Induced Immunosuppression (Université Claude Bernard Lyon 1-Hospices Civils de Lyon-bioMérieux), Edouard Herriot Hospital, Lyon, France
| | - Fabienne Venet
- Immunology Laboratory, Hospices Civils de Lyon, Edouard Herriot Hospital, Pavillon E, 5, place d'Arsonval, 69437 Cedex 03, Lyon, France.,EA 7426 Pathophysiology of Injury-Induced Immunosuppression (Université Claude Bernard Lyon 1-Hospices Civils de Lyon-bioMérieux), Edouard Herriot Hospital, Lyon, France
| | - Guillaume Monneret
- Immunology Laboratory, Hospices Civils de Lyon, Edouard Herriot Hospital, Pavillon E, 5, place d'Arsonval, 69437 Cedex 03, Lyon, France. .,EA 7426 Pathophysiology of Injury-Induced Immunosuppression (Université Claude Bernard Lyon 1-Hospices Civils de Lyon-bioMérieux), Edouard Herriot Hospital, Lyon, France.
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18
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Mendonça PHB, da Rocha RFDB, Moraes JBDB, LaRocque-de-Freitas IF, Logullo J, Morrot A, Nunes MP, Freire-de-Lima CG, Decote-Ricardo D. Canine Macrophage DH82 Cell Line As a Model to Study Susceptibility to Trypanosoma cruzi Infection. Front Immunol 2017; 8:604. [PMID: 28620374 PMCID: PMC5449653 DOI: 10.3389/fimmu.2017.00604] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Accepted: 05/08/2017] [Indexed: 12/29/2022] Open
Abstract
Trypanosoma cruzi is an obligatory intracellular protozoan parasite, and it is the etiological agent of Chagas' disease that is endemic in the Americas. In addition to humans, a wide spectrum of mammals can be infected by T. cruzi, including dogs. Dogs develop acute and chronic disease, similar to human infection. T. cruzi can infect almost all cell types and after cell invasion, the metacyclics trypomastigotes localize in the cytoplasm, where they transform into amastigotes, the replicative form of T. cruzi in mammals. After amastigote multiplication and differentiation, parasites lyse host cells and spread through the body by blood circulation. In this work, we evaluated the in vitro ability of T. cruzi to infect a canine macrophage cell line DH82 compared with RAW264.7, a murine tissue culture macrophage. Our results have shown that the T. cruzi is able to infect, replicate and differentiate in DH82 cell line. We observed that following treatment with LPS and IFN-γ DH82 cells were more resistant to infection and that resistance was not related reactive oxygen species production in our system. In this study, we also found that DH82 cells became more susceptible to T. cruzi infection when cocultured with apoptotic cells. The analysis of cytokine production has showed elevated levels of the TGF-β, IL-10, and TNF-α produced by T. cruzi-infected canine macrophages. Additionally, we demonstrated a reduced expression of the MHC class II and CD80 by infected DH82 cell line.
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Affiliation(s)
| | | | | | | | - Jorgete Logullo
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Alexandre Morrot
- Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | | | | | - Debora Decote-Ricardo
- Instituto de Veterinária, Universidade Federal Rural do Rio de Janeiro, Rio de Janeiro, Brazil
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19
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Abstract
Dying cells have an important role in the initiation of CD8+ T cell-mediated immunity. The cross-presentation of antigens derived from dying cells enables dendritic cells to present exogenous tissue-restricted or tumour-restricted proteins on MHC class I molecules. Importantly, this pathway has been implicated in multiple autoimmune diseases and accounts for the priming of tumour antigen-specific T cells. Recent data have revealed that in addition to antigen, dying cells provide inflammatory and immunogenic signals that determine the efficiency of CD8+ T cell cross-priming. The complexity of these signals has been evidenced by the multiple molecular pathways that result in cell death and that have now been shown to differentially influence antigen transfer and immunity. In this Review, we provide a detailed summary of both the passive and active signals that are generated by dying cells during their initiation of CD8+ T cell-mediated immunity. We propose that molecules generated alongside cell death pathways - inducible damage-associated molecular patterns (iDAMPs) - are upstream immunological cues that actively regulate adaptive immunity.
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20
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Kauppinen A, Paterno JJ, Blasiak J, Salminen A, Kaarniranta K. Inflammation and its role in age-related macular degeneration. Cell Mol Life Sci 2016; 73:1765-86. [PMID: 26852158 PMCID: PMC4819943 DOI: 10.1007/s00018-016-2147-8] [Citation(s) in RCA: 484] [Impact Index Per Article: 53.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2015] [Revised: 01/21/2016] [Accepted: 01/25/2016] [Indexed: 01/05/2023]
Abstract
Inflammation is a cellular response to factors that challenge the homeostasis of cells and tissues. Cell-associated and soluble pattern-recognition receptors, e.g. Toll-like receptors, inflammasome receptors, and complement components initiate complex cellular cascades by recognizing or sensing different pathogen and damage-associated molecular patterns, respectively. Cytokines and chemokines represent alarm messages for leukocytes and once activated, these cells travel long distances to targeted inflamed tissues. Although it is a crucial survival mechanism, prolonged inflammation is detrimental and participates in numerous chronic age-related diseases. This article will review the onset of inflammation and link its functions to the pathogenesis of age-related macular degeneration (AMD), which is the leading cause of severe vision loss in aged individuals in the developed countries. In this progressive disease, degeneration of the retinal pigment epithelium (RPE) results in the death of photoreceptors, leading to a loss of central vision. The RPE is prone to oxidative stress, a factor that together with deteriorating functionality, e.g. decreased intracellular recycling and degradation due to attenuated heterophagy/autophagy, induces inflammation. In the early phases, accumulation of intracellular lipofuscin in the RPE and extracellular drusen between RPE cells and Bruch's membrane can be clinically detected. Subsequently, in dry (atrophic) AMD there is geographic atrophy with discrete areas of RPE loss whereas in the wet (exudative) form there is neovascularization penetrating from the choroid to retinal layers. Elevations in levels of local and systemic biomarkers indicate that chronic inflammation is involved in the pathogenesis of both disease forms.
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Affiliation(s)
- Anu Kauppinen
- Faculty of Health Sciences, School of Pharmacy, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland.
- Department of Ophthalmology, Kuopio University Hospital, Kuopio, Finland.
| | - Jussi J Paterno
- Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland
| | - Janusz Blasiak
- Department of Molecular Genetics, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland
| | - Antero Salminen
- Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland
| | - Kai Kaarniranta
- Department of Ophthalmology, Kuopio University Hospital, Kuopio, Finland
- Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland
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21
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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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Rogge M, Yin XT, Godfrey L, Lakireddy P, Potter CA, Del Rosso CR, Stuart PM. Therapeutic Use of Soluble Fas Ligand Ameliorates Acute and Recurrent Herpetic Stromal Keratitis in Mice. Invest Ophthalmol Vis Sci 2016; 56:6377-86. [PMID: 26444718 DOI: 10.1167/iovs.15-16588] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
PURPOSE The present study was designed to test the therapeutic value of soluble FasL (sFasL) in an acute model of herpetic stromal keratitis (HSK) and, more importantly, a recurrent model of HSK using BALB/c, BALB-lpr, and National Institutes of Health (NIH) mice. METHODS Mice were infected either acutely with the KOS strain of herpes simplex virus 1 (HSV-1) or latently with the McKrae strain of HSV-1. Acutely infected mice as well as ultraviolet-B (UV-B) reactivated mice (recurrent infection) were treated with sFasL, or soluble TNF-related apoptosis inducing ligand (sTRAIL), or BSA daily or 3 times/wk by using either a combination of subconjunctival injection and topical ointment, or with topical ointment alone. These mice then were evaluated for corneal opacity and neovascularization for 6 weeks. RESULTS Following acute and recurrent HSV-1 infection, wild-type BALB/c mice treated with sFasL displayed significantly reduced incidence of corneal opacity and neovascularization compared to the control animals. However, BALB-lpr mice, which are deficient in Fas+ inflammatory cells, displayed no such differences in ocular disease, as expected. Latently infected NIH mice treated with sFasL displayed similar results. Flow cytometric analysis revealed that the corneal inflammatory infiltrate in those treated with sFasL was significantly less than in sTRAIL- or BSA-treated mice. Furthermore, corneas from sFasL-treated mice displayed relatively more cells undergoing apoptosis. CONCLUSIONS This study provides evidence that sFasL treatment has potential therapeutic benefit in reducing inflammatory infiltrate and neovascularization in primary and recurrent forms of HSK, and that it does so by augmenting the restriction of Fas+ inflammatory cells mediated by membrane FasL.
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23
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Impaired Fas-Fas Ligand Interactions Result in Greater Recurrent Herpetic Stromal Keratitis in Mice. J Immunol Res 2015; 2015:435140. [PMID: 26504854 PMCID: PMC4609448 DOI: 10.1155/2015/435140] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2015] [Accepted: 06/23/2015] [Indexed: 01/13/2023] Open
Abstract
Herpes simplex virus-1 (HSV-1) infection of the cornea leads to a potentially blinding condition termed herpetic stromal keratitis (HSK). Clinical studies have indicated that disease is primarily associated with recurrent HSK following reactivation of a latent viral infection of the trigeminal ganglia. One of the key factors that limit inflammation of the cornea is the expression of Fas ligand (FasL). We demonstrate that infection of the cornea with HSV-1 results in increased functional expression of FasL and that mice expressing mutations in Fas (lpr) and FasL (gld) display increased recurrent HSK following reactivation compared to wild-type mice. Furthermore, both gld and lpr mice took longer to clear their corneas of infectious virus and the reactivation rate for these strains was significantly greater than that seen with wild-type mice. Collectively, these findings indicate that the interaction of Fas with FasL in the cornea restricts the development of recurrent HSK.
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Jiang G, Wang Y, Yun J, Hajrasouliha AR, Zhao Y, Sun D, Kaplan HJ, Shao H. HMGB1 release triggered by the interaction of live retinal cells and uveitogenic T cells is Fas/FasL activation-dependent. J Neuroinflammation 2015; 12:179. [PMID: 26394985 PMCID: PMC4579830 DOI: 10.1186/s12974-015-0389-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2015] [Accepted: 09/02/2015] [Indexed: 11/29/2022] Open
Abstract
Background It is not clear how invading autoreactive T cells initiate the pathogenic process inside the diseased organ in T cell-mediated organ-specific autoimmune disease. In experimental autoimmune uveitis (EAU) induced by adoptive transfer of interphotoreceptor retinoid-binding protein (IRBP)-specific T cells in mice, we have previously reported that intraocular inflammation was initiated by infiltrating IRBP-specific T cells that directly interacted with retinal cells and resulted in the active release of high mobility group box 1 (HMGB1), an important member of damage associate molecular patterns (DAMPs). Furthermore, blockade of HMGB1 in our murine model reduced intraocular inflammation via suppression of IRBP-specific T cell functions. These results have demonstrated that HMGB1 is an early and critical mediator of induction of intraocular inflammation. The present study identified the cell surface molecule that triggers HMGB1 secretion. Methods Retinal explants from Fas-deficient (Faslpr) and wild-type (Wt) C57BL/6 (B6) mice were cultured with activated IRBP 1–20 peptide-specific T cells or with a Fas-activating antibody (Jo2), and then the level of HMGB1 in culture supernatants were detected by ELISA. In addition, released HMGB1 was examined in the eye of Faslpr and Wt mice after IRBP-specific T cell transfer. Uveitis was evaluated in the IRBP-specific T cell transferred Faslpr mice after recombinant HMGB1 was restored within the eye and in the IRBP-specific T cell transferred Wt mice after they were treated with a Fas antagonist (Met12). Results In contrast to retinal explants from Wt mice, those from Faslpr mice did not release HMGB1 after exposure to IRBP-specific T cells or to Jo2. The release of HMGB1 by Wt retinal explants was suppressed by Met 12. Moreover, after IRBP-specific T cell injection, Faslpr mice did not release HMGB1 in the eye or develop EAU, but intravitreous injection of HMGB1 resulted in intraocular inflammation. Finally, tEAU in Wt mice was attenuated by local treatment with Met 12. Unlike HMGB1, Fas-induced IL-1 and IL-18 were not essential for tEAU induction. Conclusion Our results show that interaction of retinal cells with infiltrating uveitogenic T cells leads to rapid release of HMGB1 via the Fas/FasL inflammatory signaling pathway.
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Affiliation(s)
- Guomin Jiang
- Department of Ophthalmology and Visual Sciences, Kentucky Lions Eye Center, University of Louisville, 301 E. Muhammad Ali Blvd., Louisville, KY, 40202, USA
| | - Yunsong Wang
- Department of Ophthalmology and Visual Sciences, Kentucky Lions Eye Center, University of Louisville, 301 E. Muhammad Ali Blvd., Louisville, KY, 40202, USA.,Department of Ophthalmology, Tangshan Gongren Hospital, Tangshan, Hebei, 063000, China
| | - Juan Yun
- Department of Ophthalmology and Visual Sciences, Kentucky Lions Eye Center, University of Louisville, 301 E. Muhammad Ali Blvd., Louisville, KY, 40202, USA.,Department of Pharmaceutical Sciences, Sullivan University College of Pharmacy, Louisville, KY, 40205, USA
| | - Amir Reza Hajrasouliha
- Department of Ophthalmology and Visual Sciences, Kentucky Lions Eye Center, University of Louisville, 301 E. Muhammad Ali Blvd., Louisville, KY, 40202, USA
| | - Yuan Zhao
- Department of Pharmaceutical Sciences, Sullivan University College of Pharmacy, Louisville, KY, 40205, USA
| | - Deming Sun
- Doheny Eye Institute, Los Angeles, CA, 90033, USA
| | - Henry J Kaplan
- Department of Ophthalmology and Visual Sciences, Kentucky Lions Eye Center, University of Louisville, 301 E. Muhammad Ali Blvd., Louisville, KY, 40202, USA
| | - Hui Shao
- Department of Ophthalmology and Visual Sciences, Kentucky Lions Eye Center, University of Louisville, 301 E. Muhammad Ali Blvd., Louisville, KY, 40202, USA.
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Mitrović S, Kelava T, Šućur A, Grčević D. Levels of Selected Aqueous Humor Mediators (IL-10, IL-17, CCL2, VEGF, FasL) in Diabetic Cataract. Ocul Immunol Inflamm 2014; 24:159-66. [PMID: 25314260 DOI: 10.3109/09273948.2014.949779] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
PURPOSE To compare levels of selected mediators in serums and aqueous humor (AH) of type 2 diabetes mellitus cataract patients with senile cataract patients, and to determine their association with postoperative corneal edema (CE). METHODS Patients (32 senile and 29 diabetic cataract) undergoing standardized phacoemulsification combined with intraocular lens implantation were recruited. CE was assessed using an ordinal scale (grade 0 to 3). IL-10, CCL2, IL-17, FasL, and VEGF were measured by ELISA. RESULTS Diabetic patients had higher AH levels of VEGF (p = .042) and IL-10 (p = .021), lower AH levels of FasL (p = .048), and higher serum levels of CCL2 (p = .002). AH levels of CCL2 were higher in diabetic patients with more severe CE at the first postoperative day (p = .012). CONCLUSIONS We found disturbed AH microenvironment in diabetic cataract, with significant changes for VEGF, IL-10, and FasL. Higher CCL2 was associated with the development of early postoperative CE in diabetic patients.
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Affiliation(s)
- Sanja Mitrović
- a Department of Ophthalmology , General Hospital, "Dr. J. Benčević," Slavonski Brod, Croatia; and Ophthalmology Clinic , Slavonski Brod , Croatia and
| | - Tomislav Kelava
- b Department of Physiology and Immunology and Laboratory for Molecular Immunology , University of Zagreb School of Medicine , Zagreb , Croatia
| | - Alan Šućur
- b Department of Physiology and Immunology and Laboratory for Molecular Immunology , University of Zagreb School of Medicine , Zagreb , Croatia
| | - Danka Grčević
- b Department of Physiology and Immunology and Laboratory for Molecular Immunology , University of Zagreb School of Medicine , Zagreb , Croatia
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Zhao H, Roychoudhury J, Doggett TA, Apte RS, Ferguson TA. Age-dependent changes in FasL (CD95L) modulate macrophage function in a model of age-related macular degeneration. Invest Ophthalmol Vis Sci 2013; 54:5321-31. [PMID: 23821188 DOI: 10.1167/iovs.13-12122] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
PURPOSE We examined the effect of aging on Fas ligand (FasL) function in a mouse model of choroidal neovascularization (CNV). METHODS Young and aged mice were laser treated to induce CNV. Bone marrow chimeras were performed between young and aged mice. FasL protein expression was examined in the eye and soluble FasL (sFasL) was measured in the blood. Young and aged mice were treated with a matrix metalloprotease (MMP) inhibitor and systemic sFasL was neutralized by antibody treatment. Macrophages from young and aged mice were tested for sFasL-mediated cytokine production and migration. RESULTS The elevated CNV response observed with aging was dependent on bone marrow-derived cells. FasL expression in the eye was increased with age, but decreased following laser treatment. Aged mice had higher levels of sFasL in the blood compared to young mice. Systemic treatment with an MMP inhibitor decreased bloodborne sFasL, and reduced CNV in young and aged mice. Systemic neutralization of sFasL reduced CNV only in aged mice. sFasL increased cytokine production in aged macrophages and proangiogenic M2 macrophages. Aged M2 macrophages had elevated Fas (CD95) expression and displayed increased migration in response to sFasL compared to M1 macrophages derived from young animals. CONCLUSIONS Age modulates FasL function where increased MMP cleavage leads to a loss of function in the eye. The released form of FasL (sFasL) preferentially induces the migration of proangiogenic M2 macrophages into the laser lesions and increases proangiogenic cytokines promoting CNV. FasL may be a viable target for therapeutic intervention in aged-related neovascular disease.
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Affiliation(s)
- Hui Zhao
- Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri 63110, USA
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Abstract
Immune privilege protects vital organs and their functions from the destructive interference of inflammation. Because the eye is easily accessible for surgical manipulation and for assessing and imaging the outcomes, the eye has been a major tissue for the study of immune privilege. Here, we focus on the immune regulatory mechanisms in the posterior eye, in part, because loss of immune privilege may contribute to development of certain retinal diseases in the aging population. We begin with a background in immune privilege and then focus on the select regulatory mechanisms that have been studied in the posterior eye. The review includes a description of the immunosuppressive environment, regulatory surface molecules expressed by cells in the eye, types of cells that participate in immune regulation and finally, discusses animal models of retinal laser injury in the context of mechanisms that overcome immune privilege.
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Affiliation(s)
- Joan Stein-Streilein
- Department of Ophthalmology, Schepens Eye Research Institute, Mass Eye & Ear, Harvard Medical School, Boston, MA 02114, USA.
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Ravishankar B, McGaha TL. O death where is thy sting? Immunologic tolerance to apoptotic self. Cell Mol Life Sci 2013; 70:3571-89. [PMID: 23377225 DOI: 10.1007/s00018-013-1261-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2012] [Revised: 12/14/2012] [Accepted: 01/03/2013] [Indexed: 12/22/2022]
Abstract
In higher organisms, innate scavenging cells maintain physiologic homeostasis by removal of the billions of apoptotic cells generated on a daily basis. Apoptotic cell removal requires efficient recognition and uptake by professional and non-professional phagocytic cells, which are governed by an array of soluble and apoptotic cell-integral signals resulting in immunologically silent clearance. While apoptosis is associated with profound suppression of adaptive and innate inflammatory immunity, we have only begun to scratch the surface in understanding how immunologic tolerance to apoptotic self manifest at either the molecular or cellular level. In the last 10 years, data has emerged implicating professional phagocytes, most notably stromal macrophages and CD8α(+)CD103(+) dendritic cells, as critical in initiation of the regulatory cascade that will ultimately lead to long-term whole-animal immune tolerance. Importantly, recent work by our lab and others has shown that alterations in apoptotic cell perception by the innate immune system either by removal of critical phagocytic sentinels in secondary lymphoid organs or blockage of immunosuppressive pathways leads to pronounced inflammation with a breakdown of tolerance towards self. This challenges the paradigm that apoptotic cells are inherently immunosuppressive, suggesting that apoptotic cell tolerance is a "context-dependent" event.
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Affiliation(s)
- Buvana Ravishankar
- Cancer Immunology, Inflammation, and Tolerance Program, GRU Cancer Center, Georgia Regents University, Building CN4143, 1120 15th Street, Augusta, GA, 30904, USA
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Dhingra S, Huang XP, Li RK. Challenges in allogeneic mesenchymal stem cell-mediated cardiac repair. Trends Cardiovasc Med 2012; 20:263-8. [PMID: 22433652 DOI: 10.1016/j.tcm.2011.12.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Autologous mesenchymal stem cells (MSCs) have been proven safe in phase I and II clinical trials in patients who have suffered a myocardial infarction. However, their potential for proliferation and differentiation decreases with age, which limits their efficacy in elderly patients. Allogeneic MSCs offer several key advantages over autologous MSCs, including a high regenerative potential and availability for clinical use without the delay required for expansion. It was believed that allogeneic MSCs were immune privileged and thus able to escape the recipient's immune system. In several preclinical studies, allogeneic MSCs were successful in regenerating the myocardium, and the transplanted MSCs improved heart function early after implantation. However, the long-term ability of allogeneic MSCs to preserve heart function is limited because of a transition from an immune privileged to an immunogenic phenotype after the cells differentiate. The initial phase I/II clinical study using allogeneic MSCs in patients with acute myocardial infarction was safe, and no side effects were observed. However, the long-term safety and efficacy of allogeneic MSCs remain to be established. In this review, we discuss the challenges of using allogeneic MSCs for cardiac repair and present strategies to prevent the immune rejection of allogeneic MSCs to increase their potential for use in cardiac patients.
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Affiliation(s)
- Sanjiv Dhingra
- Division of Cardiovascular Surgery and Toronto General Research Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada M5G 1L7
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30
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McKenna KC, Previte DM. Influence of CD8+ T regulatory cells on intraocular tumor development. Front Immunol 2012; 3:303. [PMID: 23060881 PMCID: PMC3460369 DOI: 10.3389/fimmu.2012.00303] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2012] [Accepted: 09/10/2012] [Indexed: 11/13/2022] Open
Abstract
The interior of the eye, or uvea, is a site of immune privilege where certain immune responses are attenuated or completely excluded to protect non-regenerating tissues essential for vision. One consequence of this immunoregulation is compromised immune mediated elimination of intraocular tumors. For example, certain murine tumor cell lines which are rejected by host immune responses when transplanted in the skin grow progressively when placed in the anterior chamber (a.c.) of the eye. Progressive ocular tumor growth occurs despite induction of tumor-specific CD8+ T cell responses capable of eliminating a subsequent tumor challenge in the skin or opposite eye. Why these CD8+ T effectors fail to eliminate established ocular tumors is not known. It is well appreciated that growth of tumors in the a.c. induces the generation of immunosuppressive CD8+ T regulatory (Treg) cells. However, the contribution of CD8+ Treg in ocular tumor progression remains unclear. Several studies indicate that these CD8+ Treg target responding CD4+ T cells to inhibit their induction of macrophage-dependent delayed type hypersensitivity (DTH) responses to tumor antigens (Ags). However, induction of tumor-specific CD4+ T cell responses does not assure intraocular tumor elimination. This review is focused on how CD8+ Treg could influence the tumoricidal activity of ocular tumor-specific CD8+ T effector cells.
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Affiliation(s)
- Kyle C McKenna
- Departments of Ophthalmology and Immunology/Medicine, University of Pittsburgh, University of Pittsburgh Cancer Institute Pittsburgh, PA, USA
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31
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Nita M, Strzałka-Mrozik B, Grzybowski A, Romaniuk W, Mazurek U. Ophthalmic transplantology: posterior segment of the eye--part II. Med Sci Monit 2012; 18:RA97-103. [PMID: 22648265 PMCID: PMC3560715 DOI: 10.12659/msm.882868] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Background Transplants of the retina are among the new strategies being used in the treatment of genetic and degenerative macular diseases. Moreover, various cell cultures are being tested to treat retinal disorders. Material/Methods Literature dated from 2004 to 2011 was comprehensively examined via Medline and PubMed searches for the following terms: auto-, homo-, heterologous transplantation, retina, stem cells, cultivated cells. Results Tissue and cell therapy of retinal diseases are reviewed, including full-thickness retina/retinal pigment epithelium (RPE)/choroid graft; full and partial thickness RPE/choroid complex grafts; RPE/Bruch membrane complex graft; and RPE, iris pigment epithelium and stem cell grafts. Recommendations for transplants, as well as the benefits and weaknesses of specific techniques in retina transplants, are discussed. Conclusions Auto- and allogenic transplants of a full or partial thickness retina/RPE/Bruch membrane/choroid complex represent an alternative treatment offered to patients with some macular diseases. Stem cell transplantation to reconstruct and regenerate the macula requires further biomolecular and animal research studies.
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Affiliation(s)
- Małgorzata Nita
- Domestic and Specialized Medicine Centre Dilmed, Katowice, Poland
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32
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Wraith DC, Nicholson LB. The adaptive immune system in diseases of the central nervous system. J Clin Invest 2012; 122:1172-9. [PMID: 22466659 DOI: 10.1172/jci58648] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Tissues of the CNS, such as the brain, optic nerves, and spinal cord, may be affected by a range of insults including genetic, autoimmune, infectious, or neurodegenerative diseases and cancer. The immune system is involved in the pathogenesis of many of these, either by causing tissue damage or alternatively by responding to disease and contributing to repair. It is clearly vital that cells of the immune system patrol the CNS and protect against infection. However, in contrast to other tissues, damage caused by immune pathology in the CNS can be irreparable. The nervous and immune systems have, therefore, coevolved to permit effective immune surveillance while limiting immune pathology. Here we will consider aspects of adaptive immunity in the CNS and the retina, both in the context of protection from infection as well as cancer and autoimmunity, while focusing on immune responses that compromise health and lead to significant morbidity.
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Affiliation(s)
- David C Wraith
- School of Clinical Sciences, University of Bristol, Bristol, United Kingdom.
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Koopman G, Beenhakker N, Hofman S, Walther-Jallow L, Mäkitalo B, Mooij P, Anderson J, Verschoor E, Bogers WM, Heeney JL, Spetz AL. Immunization with apoptotic pseudovirus transduced cells induces both cellular and humoral responses: A proof of concept study in macaques. Vaccine 2012; 30:2523-34. [DOI: 10.1016/j.vaccine.2012.01.082] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2011] [Revised: 01/11/2012] [Accepted: 01/29/2012] [Indexed: 11/29/2022]
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Characterization of Effector Memory CD8+ T Cells in the Synovial Fluid of Rheumatoid Arthritis. J Clin Immunol 2012; 32:709-20. [DOI: 10.1007/s10875-012-9674-3] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2011] [Accepted: 02/15/2012] [Indexed: 01/06/2023]
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Stevenson W, Cheng SF, Dastjerdi MH, Ferrari G, Dana R. Corneal neovascularization and the utility of topical VEGF inhibition: ranibizumab (Lucentis) vs bevacizumab (Avastin). Ocul Surf 2012; 10:67-83. [PMID: 22482468 DOI: 10.1016/j.jtos.2012.01.005] [Citation(s) in RCA: 126] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2011] [Revised: 01/10/2012] [Accepted: 01/14/2012] [Indexed: 12/21/2022]
Abstract
Corneal avascularity is necessary for the preservation of optimal vision. The cornea maintains a dynamic balance between pro- and antiangiogenic factors that allows it to remain avascular under normal homeostatic conditions; however, corneal avascularity can be compromised by pathologic conditions that negate the cornea's "angiogenic privilege." The clinical relevance of corneal neovascularization has long been recognized, but management of this condition has been hindered by a lack of safe and effective therapeutic modalities. Herein, the etiology, epidemiology, pathogenesis, and treatment of corneal neovascularization are reviewed. Additionally, the authors' recent findings regarding the clinical utility of topical ranibizumab (Lucentis®) and bevacizumab (Avastin®) in the treatment of corneal neovascularization are summarized. These findings clearly indicate that ranibizumab and bevacizumab are safe and effective treatments for corneal neovascularization when appropriate precautions are observed. Although direct comparisons are not conclusive, the results suggest that ranibizumab may be modestly superior to bevacizumab in terms of both onset of action and degree of efficacy. In order to justify the increased cost of ranibizumab, it will be necessary to demonstrate meaningful treatment superiority in a prospective, randomized, head-to-head comparison study.
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Affiliation(s)
- William Stevenson
- Schepens Eye Research Institute, Massachusetts Eye & Ear Infirmary, Harvard Medical School, Boston, MA 02114, USA
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36
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Griffith TS, Ferguson TA. Cell death in the maintenance and abrogation of tolerance: the five Ws of dying cells. Immunity 2011; 35:456-66. [PMID: 22035838 DOI: 10.1016/j.immuni.2011.08.011] [Citation(s) in RCA: 78] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2011] [Revised: 08/11/2011] [Accepted: 08/29/2011] [Indexed: 02/07/2023]
Abstract
The mammalian immune system continually faces death in the form of its own dead and dying cells that arise during normal tissue turnover, infections, cellular damage, and cancer. Complex decisions must then be made that will permit a protective response to pathogens, while at the same time destroying tumors but not attacking vital systems of the host that could lead to autoimmunity. By using an investigative technique termed the five Ws (who, what, when, where, and why), we will examine how the immune system responds to antigens generated via cell death. This analysis will give us a better understanding of the molecular differences fundamental to tolerogenic or immunogenic cell death, the cells that sense and react to the dead cells, and the consequences of these fundamental elements on the maintenance or abrogation of tolerance.
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Affiliation(s)
- Thomas S Griffith
- Department of Urology, University of Minnesota, Minneapolis, MN 55455, USA.
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37
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Morris JE, Zobell S, Yin XT, Zakeri H, Summers BC, Leib DA, Stuart PM. Mice with mutations in Fas and Fas ligand demonstrate increased herpetic stromal keratitis following corneal infection with HSV-1. THE JOURNAL OF IMMUNOLOGY 2011; 188:793-9. [PMID: 22156346 DOI: 10.4049/jimmunol.1102251] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
HSV-1 infection of the cornea leads to a potentially blinding immunoinflammatory lesion of the cornea, termed herpetic stromal keratitis. It has also been shown that one of the factors limiting inflammation of the cornea is the presence of Fas ligand (FasL) on corneal epithelium and endothelium. In this study, the role played by FasL expression in the cornea following acute infection with HSV-1 was determined. Both BALB/c and C57BL/6 (B6) mice with HSV-1 infection were compared with their lpr and gld counterparts. Results indicated that mice bearing mutations in the Fas Ag (lpr) displayed the most severe disease, whereas the FasL-defective gld mouse displayed an intermediate phenotype. It was further demonstrated that increased disease was due to lack of Fas expression on bone marrow-derived cells. Of interest, although virus persisted slightly longer in the corneas of mice bearing lpr and gld mutations, the persistence of infectious virus in the trigeminal ganglia was the same for all strains infected. Further, B6 mice bearing lpr and gld mutations were also more resistant to virus-induced mortality than were wild-type B6 mice. Thus, neither disease nor mortality correlated with viral replication in these mice. Collectively, the findings indicate that the presence of FasL on the cornea restricts the entry of Fas(+) bone marrow-derived inflammatory cells and thus reduces the severity of HSK.
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Affiliation(s)
- Jessica E Morris
- Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA
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38
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Abstract
Immune responses during infection, injury, and cancer proceed in the presence of tissue injury and cell death. Consequently, the system must deal with its own dead cells while it determines the appropriate response to the invader. As apoptotic cells are known to induce immune tolerance and necrotic cells can be potent stimulators of immunity, this decision becomes more complex. The key to understanding the immunologic choices made during cell death is to examine the mechanisms of tolerance induction by dying cells and then relate them to the mechanisms of immunity. Ideally, immunogenic cell death should be directed toward tumor cells and infected cells, whereas tolerogenic cell death should be associated with preventing unwanted immune responses to self. In this review, we discuss how the decision is made by focusing on the biochemical process of cell death and how its key components can influence both tolerance and immunity.
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Affiliation(s)
- Thomas A Ferguson
- Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA.
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Marginal zone macrophages suppress innate and adaptive immunity to apoptotic cells in the spleen. Blood 2011; 117:5403-12. [PMID: 21444914 DOI: 10.1182/blood-2010-11-320028] [Citation(s) in RCA: 123] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Marginal zone macrophages (MZMs) are a small subset of specialized splenic macrophages known to interact with apoptotic material entering the spleen from circulation. To evaluate whether MZMs regulate immunity to apoptotic material we depleted MZMs and assessed innate and adaptive immune responses to apoptotic cells administered systemically. MZM depletion altered the spatial localization of apoptotic cells, which accumulated in T-cell areas of the lymphoid follicles. MZM depletion also enhanced phagocytosis of apoptotic cells by red pulp (CD68(+)F4/80(+)) macrophages, which expressed increased CD86, MHCII, and CCR7. MZM depletion led to increased production of proinflammatory cytokines and enhanced lymphocyte responsiveness to apoptotic cell antigens. Furthermore, we found that MZM depletion accelerated autoimmune disease progression in mice genetically prone to systemic lupus erythematosus and caused significant mortality in wild-type mice repeatedly exposed to exogenous apoptotic thymocytes. These findings support the hypothesis that MZMs are central in the clearance of apoptotic cells to minimize the immunogenicity of autoantigens.
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Griffith TS, Brincks EL, Gurung P, Kucaba TA, Ferguson TA. Systemic immunological tolerance to ocular antigens is mediated by TRAIL-expressing CD8+ T cells. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2011; 186:791-8. [PMID: 21169546 PMCID: PMC3075597 DOI: 10.4049/jimmunol.1002678] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Systemic immunological tolerance to Ag encountered in the eye restricts the formation of potentially damaging immune responses that would otherwise be initiated at other anatomical locations. We previously demonstrated that tolerance to Ag administered via the anterior chamber (AC) of the eye required Fas ligand-mediated apoptotic death of inflammatory cells that enter the eye in response to the antigenic challenge. Moreover, the systemic tolerance induced after AC injection of Ag was mediated by CD8(+) regulatory T cells. This study examined the mechanism by which these CD8(+) regulatory T cells mediate tolerance after AC injection of Ag. AC injection of Ag did not prime CD4(+) T cells and led to increased TRAIL expression by splenic CD8(+) T cells. Unlike wild-type mice, Trail(-/-) or Dr5(-/-) mice did not develop tolerance to Ag injected into the eye, even though responding lymphocytes underwent apoptosis in the AC of the eyes of these mice. CD8(+) T cells from Trail(-/-) mice that were first injected via the AC with Ag were unable to transfer tolerance to naive recipient wild-type mice, but CD8(+) T cells from AC-injected wild-type or Dr5(-/-) mice could transfer tolerance. Importantly, the transferred wild-type (Trail(+/+)) CD8(+) T cells were also able to decrease the number of infiltrating inflammatory cells into the eye; however, Trail(-/-) CD8(+) T cells were unable to limit the inflammatory cell ingress. Together, our data suggest that "helpless" CD8(+) regulatory T cells generated after AC injection of Ag enforce systemic tolerance in a TRAIL-dependent manner to inhibit inflammation in the eye.
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Affiliation(s)
- Thomas S Griffith
- Department of Urology, University of Iowa, Iowa City, IA 52242, USA.
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Gordon N, Kleinerman ES. Aerosol therapy for the treatment of osteosarcoma lung metastases: targeting the Fas/FasL pathway and rationale for the use of gemcitabine. J Aerosol Med Pulm Drug Deliv 2010; 23:189-96. [PMID: 20528149 DOI: 10.1089/jamp.2009.0812] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Lung metastases are the main cause of death in patients with osteosarcoma (OS). Salvage chemotherapy has been largely unsuccessful in improving the long-term survival of these patients. Understanding the mechanisms that play a role in the metastatic process may identify new therapeutic strategies. We have demonstrated that the cell surface Fas expression, the Fas/FasL signaling pathway, and the constitutive expression of FasL in the lung microenvironment play a critical role in the metastatic potential of OS cells. Here we review the status of Fas expression in two sets of OS cells, human SAOS and LM7 and murine K7 and K7M2, which differ in their ability to metastasize to the lungs. We demonstrated that Fas expression inversely correlated with metastatic potential. Evaluation of Fas expression in a set of lung metastases from patients demonstrated low or no Fas expression consistent with our hypothesis that Fas+ osteosarcoma cells cannot form metastases. The absence of FasL in the lung allows Fas+ osteosarcoma cells to form metastases indicating that the microenvironment is an important contributor to the metastatic potential of osteosarcoma cells. Disruption of the signal transduction pathway using Fas-associated death domain dominant negative (FDN) also allowed Fas+ cells to form lung metastases. Aerosol Gemcitabine (GCB) upregulated Fas expression and induced tumor regression in wild-type Balb/c mice but not Fas L-deficient mice. In conclusion, Fas constitutes an early defense mechanism that allows Fas+ tumor cells to undergo apoptosis when in contact with constitutive FasL in the lung. Fas- cells or cells with a corrupted Fas pathway evade this defense mechanism and form lung metastases. The aerosol delivery of chemotherapeutic agents that upregulate Fas expression may benefit patients with established pulmonary metastases.
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Affiliation(s)
- Nancy Gordon
- Children's Cancer Hospital, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA
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Moldenhauer LM, Hayball JD, Robertson SA. Utilising T cell receptor transgenic mice to define mechanisms of maternal T cell tolerance in pregnancy. J Reprod Immunol 2010; 87:1-13. [DOI: 10.1016/j.jri.2010.05.007] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2010] [Revised: 05/19/2010] [Accepted: 05/31/2010] [Indexed: 12/21/2022]
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Gordon N, Kleinerman ES. The role of Fas/FasL in the metastatic potential of osteosarcoma and targeting this pathway for the treatment of osteosarcoma lung metastases. Cancer Treat Res 2010; 152:497-508. [PMID: 20213411 DOI: 10.1007/978-1-4419-0284-9_29] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Pulmonary metastases remain the main cause of death in patients with Osteosarcoma (OS). In order to identify new targets for treatment, our laboratory has focused on understanding the biological properties of the tumor microenvironment that contribute to or interfere with metastasis. Dysfunction of the Fas/FasL signaling pathway has been implicated in tumor development, and progression. Here we describe the status of Fas expression in murine nonmetastatic K7 and metastatic K7M2 cells and human nonmetastatic SAOS and LM2 and metastatic LM6 OS cells. We demonstrated that Fas expression correlates inversely with metastatic potential. Pulmonary metastases from patients were uniformly Fas- supporting the importance of Fas expression to the metastatic potential. Since FasL is constitutively expressed in the lung, our data suggests that Fas+ tumor cells undergo apoptosis and are cleared from the lung. By contrast, Fas- tumor cells evade this host defense mechanism and form lung metastases. We confirmed these findings by blocking the Fas pathway using Fas Associated Death Domain Dominant-Negative (FDN). Fas+ cells transfected with FDN were not sensitive to FasL, showed delayed clearance and formed lung metastases. Fas+ cells were also able to form lung metastases in FasL-deficient mice. Using our mouse model systems, we demonstrated that aerosol treatment with liposomal 9-Nitrocamptothecin and Gemcitabine (chemotherapeutic agents known to upregulate Fas expression) increased Fas expression and induced tumor regression in wild type mice. Lung metastases in FasL deficient mice did not respond to the treatment. We conclude that Fas is an early defense mechanism responsible for clearing invading Fas+ tumor cells from the lung. Fas- cells or cells with a nonfunctional Fas pathway evade this defense mechanism and form lung metastases. Therapy that induces Fas expression may therefore be effective in patients with established OS lung metastases. Aerosol delivery of these agents is an ideal way to target treatment to the lung.
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Affiliation(s)
- Nancy Gordon
- Division of Pediatrics, Children's Cancer Hospital, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit #87, Houston, TX 77030-4009, USA.
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Janssen EM, Lemmens EE, Gour N, Reboulet RA, Green DR, Schoenberger SP, Pinkoski MJ. Distinct roles of cytolytic effector molecules for antigen-restricted killing by CTL in vivo. Immunol Cell Biol 2010; 88:761-5. [PMID: 20309009 PMCID: PMC2939217 DOI: 10.1038/icb.2010.37] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Cytotoxic T lymphocytes (CTLs) represent one of the front lines of defense for the immune system, killing virus-infected and tumor-transformed cells. CTL use at least two mechanisms to induce apoptosis in their targets, one mediated by perforin and granzymes, and the other triggered by the death ligand, CD95 ligand (CD95L). Here, we used an in vivo cytotoxicity assay to measure specific clearance of antigen-bearing target cells in mice that had previously been immunized with noninfectious cell-associated antigens. We found that perforin was dispensable for efficient clearance of antigen-bearing cells from immunized mice, but only if CD95/CD95L was functional; however, there was a delay in target cell clearance in the absence of perforin. In addition, we observed ∼35% target cell clearance in the absence of both perforin and CD95L, which was only slightly abrogated in the presence of a neutralizing anti-tumor necrosis factor (TNF) antibody. The presence of a dominant negative Fas-associated death domain (FADD) did not block target cell clearance and therefore cannot be attributed to known death receptors. Taken together, these data suggest that perforin- and CD95L-dependent killing are complementary at early time points, each can compensate for the absence of the other at later time points, and that there is an additional component of antigen-restricted CTL killing independent of perforin, CD95L, and TNFα.
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Affiliation(s)
- Edith M Janssen
- Division of Molecular Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
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45
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Gurung P, Kucaba TA, Schoenberger SP, Ferguson TA, Griffith TS. TRAIL-expressing CD8+ T cells mediate tolerance following soluble peptide-induced peripheral T cell deletion. J Leukoc Biol 2010; 88:1217-25. [PMID: 20807702 DOI: 10.1189/jlb.0610343] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Peripheral tolerance controls the action of self-reactive T cells that escape thymic deletion. We showed previously that deletion of Ag-specific CD4+ T cells induced a CD8+ T(reg) population that maintained tolerance by deleting T cells with the same Ag specificity. The present study explored the mechanism of action of these CD8+ T(reg). Following OT-II T cell deletion by soluble OVA₃₂₃₋₃₃₉, B6 mice were unresponsive to challenge after CFA/OVA immunization, and Trail⁻/⁻ or Dr5⁻/⁻ mice were immune, although all strains displayed similar OT-II peripheral deletion. Interestingly, B6 mice remained tolerant to OVA even after a second infusion of OT-II T cells. Tolerance could be transferred to naïve recipients using CD8+ T cells from B6 or Dr5⁻/⁻ mice that experienced peptide-induced peripheral OT-II deletion but not from Trail⁻/⁻ mice. Subsequent investigation found that the mechanism of action of the CD8+ T(reg) was TRAIL-mediated OT-II T cell deletion in a TCR-specific manner. Furthermore, the tolerance was transient, as it was established by 14 days after peptide injection but lost by Day 56. Together, these data provide evidence to suggest that the mechanism behind transient peripheral tolerance induced following T cell deletion is the cytotoxic activity of TRAIL-expressing CD8+ T(reg).
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Affiliation(s)
- Prajwal Gurung
- Department of Urology, University of Iowa, Iowa City, Iowa 52242-1089, USA
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Ke Y, Sun D, Jiang G, Kaplan HJ, Shao H. PD-L1(hi) retinal pigment epithelium (RPE) cells elicited by inflammatory cytokines induce regulatory activity in uveitogenic T cells. J Leukoc Biol 2010; 88:1241-9. [PMID: 20739617 DOI: 10.1189/jlb.0610332] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
We previously reported that after exposure to inflammatory cytokines, such as IL-17 and IFN-γ, RPE cells express increased amounts of suppressor of cytokine signaling, leading to general suppression of the inflammatory response. Here, we demonstrate that RPE cells expressed increased levels of PD-L1 in response to IL-17, IFN-γ, or Poly I:C. These PD-L1(hi) RPE cells inhibited the pathogenic activities of IRBP-specific T cells, which usually induced uveitis when injected into naïve mice (EAU). The suppressed pathogenicity of these uveitogenic T cells after exposure to PD-L1(hi) RPE cells could be partially reversed by anti-PD-L1 antibodies. Nevertheless, IRBP-specific T cells pre-exposed to PD-L1(hi) RPE cells displayed substantial suppressor activity, which strongly inhibited the activation of fresh IRBP-Teffs in response to subsequent antigenic challenge and when transferred into naïve mice, inhibited the induction of EAU by IRBP-Teff transfer. These findings suggest that inflammatory cytokine-triggered up-regulation of PD-L1 on RPE constitutes a critical factor for inducing infiltrated uveitogenic T cells with regulatory activities, which may accelerate the natural resolution of T cell-mediated intraocular inflammation.
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Affiliation(s)
- Yan Ke
- Department of Ophthalmology and Vision Sciences, University of Louisville, 301 E. Muhammad Ali Blvd., Louisville, KY 40202, USA.
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The role of FasL and Fas in health and disease. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2010; 647:64-93. [PMID: 19760067 DOI: 10.1007/978-0-387-89520-8_5] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The FS7-associated cell surface antigen (Fas, also named CD95, APO-1 or TNFRSF6) attracted considerable interest in the field of apoptosis research since its discovery in 1989. The groups of Shin Yonehara and Peter Krammer were the first reporting extensive apoptotic cell death induction upon treating cells with Fas-specific monoclonal antibodies.1,2 Cloning of Fas3 and its ligand,4,5 FasL (also known as CD178, CD95L or TNFSF6), laid the cornerstone in establishing this receptor-ligand system as a central regulator of apoptosis in mammals. Therapeutic exploitation of FasL-Fas-mediated cytotoxicity was soon an ambitous goal and during the last decade numerous strategies have been developed for its realization. In this chapter, we will briefly introduce essential general aspects of the FasL-Fas system before reviewing its physiological and pathophysiological relevance. Finally, FasL-Fas-related therapeutic tools and concepts will be addressed.
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Unsinger J, Kazama H, McDonough JS, Griffith TS, Hotchkiss RS, Ferguson TA. Sepsis-induced apoptosis leads to active suppression of delayed-type hypersensitivity by CD8+ regulatory T cells through a TRAIL-dependent mechanism. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2010; 184:6766-72. [PMID: 20483771 PMCID: PMC2887093 DOI: 10.4049/jimmunol.0904054] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Patients who survive severe sepsis often display severely compromised immune function. One hallmark of such immune suppression in septic patients is an impaired delayed-type hypersensitivity (DTH) response, manifested by a loss of skin testing to recall Ags. Because sepsis induces significant apoptosis in lymphoid and myeloid cells, and apoptotic cells are themselves tolerogenic, we tested the hypothesis that suppression of DTH is mediated by tolerogenic properties of the apoptotic cells generated during sepsis. Mice subjected to cecal ligation and puncture demonstrated a loss of DTH for the 7 d following cecal ligation and puncture; however, the immune response returned to normal by day 10. Blocking sepsis-induced apoptosis via Bcl-2 overexpression or Bim deficiency prevented the loss of DTH. Importantly, injection of apoptotic cells into Bim-/- mice prevented an effective DTH response, thereby suggesting a causal link between apoptotic cells and immune suppression. Surprisingly, when TRAIL null mice were examined, we found that these animals had significant apoptosis but retained their DTH responses. Further studies revealed that apoptotic cells generated during sepsis induced a CD8+ regulatory T cell that suppressed DTH by TRAIL production. These results establish a link between apoptotic cells and immune suppression during sepsis and suggest TRAIL may be a viable therapeutic target for boosting the adaptive immune response following sepsis.
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Affiliation(s)
- Jacqueline Unsinger
- Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110
| | - Hirotaka Kazama
- Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110
| | | | - Thomas S. Griffith
- Department of Urology and Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, IA 52242
| | - Richard S. Hotchkiss
- Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110
| | - Thomas A. Ferguson
- Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110
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Weinlich R, Brunner T, Amarante-Mendes GP. Control of death receptor ligand activity by posttranslational modifications. Cell Mol Life Sci 2010; 67:1631-42. [PMID: 20306114 PMCID: PMC11115959 DOI: 10.1007/s00018-010-0289-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2010] [Accepted: 01/20/2010] [Indexed: 01/26/2023]
Abstract
The death receptor ligands are involved in many physiological and pathological processes involving triggering of apoptosis, inflammation, proliferation, and activation. The expression of these molecules is reported to be tightly regulated at the transcriptional level. However, over the last few years, an increasing number of data demonstrated that the control of transcription is only one of the mechanisms that manage the expression of the death receptor ligands. Thus, this review is focused on posttranslational regulation of the three main members of this family, namely FasL, TNF-alpha, and TRAIL. We discuss here the importance of distribution, storage, and degranulation of these molecules, as well as their shedding by proteases on the control of death receptor ligands expression and activity.
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Affiliation(s)
- R Weinlich
- Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil.
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Prognostic significance of CD95, P53, and BCL2 expression in extranodal non-Hodgkin’s lymphoma. Ann Hematol 2010; 89:889-96. [DOI: 10.1007/s00277-010-0945-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2009] [Accepted: 03/15/2010] [Indexed: 11/26/2022]
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