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Andrew D Dick - One of the best experts on this subject based on the ideXlab platform.
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The B subunit of Escherichia coli heat-labile enterotoxin inhibits Th1 but not Th17 cell responses in established experimental autoimmune Uveoretinitis
2013Co-Authors: Ben J. E. Raveney, Marie-laure Aknin, Bronwen R. Burton, Lindsay B. Nicholson, Neil A. Williams, David A. Copl, Claire Richards, Emma Kerr, Andrew D DickAbstract:PURPOSE. To investigate the efficacy of the B subunit of Escherichia coli heat-labile enterotoxin (EtxB) in the treatment of ocular autoimmune disease. Murine experimental autoimmune Uveoretinitis (EAU) is an animal model of autoimmune posterior uveitis initiated by retinal antigen-specific Th1 and Th17 CD4 � T cells, which activate myeloid cells, inducing retinal damage. EtxB is a potent immune modulator that ameliorates other Th1-mediated autoimmune diseases, enhancing regulatory T-cell activity. METHODS. EAU was induced in B10.RIII mice by immunization with peptide hIRBP 161-180. Disease severity was measured by clinical and histologic assessment, and functional responses of macrophages (M�s) and T cells were assessed, both in vivo and in cocultures in vitro. EtxB was administered intranasally daily for 4 days, starting either 3 days before or 3 days after EA
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The Journal of Immunology A Selective Role for the TNF p55 Receptor in Autocrine Signaling following IFN- � Stimulation in Experimental
2013Co-Authors: Autoimmune Uveoretinitis, Lindsay B. Nicholson, Claudia J. Calder, Andrew D DickAbstract:IFN- � stimulates macrophage activation and NO production, which leads to destruction of the retina in experimental autoimmune Uveoretinitis. In this study, we investigate the mechanism of disease resistance in TNF p55 receptor-deficient animals. We show that although T cell priming is relatively unaffected, macrophages lacking the TNF p55 receptor fail to produce NO following IFN- � stimulation because of a requirement for autocrine TNF- � signaling through the TNF p55 receptor. In contrast to the impaired activation of NO synthesis, MHC class II up-regulation was indistinguishable in wild-type and TNFRp55 �/ � mice stimulated with IFN-�. These defects could be overcome by stimulating macrophages with LPS. Together, these results show that selected aspects of IFN- � activation are controlled by autocrine secretion of TNF-�, but that this control is lost in the presence of signals generated by pathogen-associated molecular patterns recognizing receptors. The Journal of Immunology, 2005, 175: 6286–6293. Studies of experimental autoimmune Uveoretinitis (EAU) 3 have provided abundant evidence that TNF- � plays a pivotal role in the pathogenesis of intraocular inflammation and retinal tissue destruction. EAU is an organ-specific autoimmune disease in which Th1 CD4 � T cells, directed toward retinal Ags, produce cytokines, such as IFN-�, which activate residen
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The Clinical Time-Course of Experimental Autoimmune Uveoretinitis Using Topical Endoscopic Fundal Imaging with Histologic and Cellular Infiltrate Correlation
2013Co-Authors: David A. Copl, Ben J. E. Raveney, Lindsay B. Nicholson, Michael S. Wertheim, John W. Armitage, Andrew D DickAbstract:PURPOSE. EAU is an established preclinical model for assessment of immunotherapeutic efficacy toward translation of therapy for posterior uveitis. Reliable screening of clinical features that correlate with underlying retinal changes and damage has not been possible to date. This study was undertaken to describe, validate, and correlate topical endoscopic fundus imaging (TEFI) with histologic features of murine experimental autoimmune Uveoretinitis (EAU), with the intent of generating a rapid noninvasive panretinal assessment of ocular inflammation. METHODS. EAU was induced in B10.RIII mice by immunization with the peptide RBP-3161-180. The clinical disease course (days 0–63) was monitored and documented using TEFI. Disease severity and pathology were confirmed at various time points by histologic assessment. The composition of the cell infiltrate was also examined and enumerated by flow cytometry
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persistent inflammation subverts thrombospondin 1 induced regulation of retinal angiogenesis and is driven by ccr2 ligation
American Journal of Pathology, 2012Co-Authors: Mei Chen, John V Forrester, David A. Copland, Jiawu Zhao, Jian Liu, Andrew D DickAbstract:Neovascular retinal disease is a leading cause of blindness orchestrated by inflammatory responses. Although noninfectious Uveoretinitis is mediated by CD4 + T cells, in the persistent phase of disease, angiogenic responses are observed, along with degeneration of the retina. Full clinical manifestation relies on myeloid-derived cells, which are phenotypically distinct from, but potentially sharing common effector responses to age-related macular degeneration. To interrogate inflammation-mediated angiogenesis, we investigated experimental autoimmune Uveoretinitis, an animal model for human uveitis. After the initial acute phase of severe inflammation, the retina sustains a persistent low-grade inflammation with tissue-infiltrating leukocytes for over 4 months. During this persistent phase, angiogenesis is observed as retinal neovascular membranes that arise from inflamed venules and postcapillary venules, increase in size as the disease progresses, and are associated with infiltrating arginase-1 + macrophages. In the absence of thrombospondin-1, retinal neovascular membranes are markedly increased and are associated with arginase-1 − CD68 + macrophages, whereas deletion of the chemokine receptor CCR2 resulted in reduced retinal neovascular membranes in association with a predominant neutrophil infiltrate. CCR2 is important for macrophage recruitment to the retina in experimental autoimmune Uveoretinitis and promotes chronicity in the form of a persistent angiogenesis response, which in turn is regulated by constitutive expression of angiogenic inhibitors like thrombospondin-1. This model offers a new platform to dissect the molecular and cellular pathology of inflammation-induced ocular angiogenesis.
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dendritic cell physiology and function in the eye
Immunological Reviews, 2010Co-Authors: John V Forrester, Andrew D Dick, Lucia Kuffova, Paul G McmenaminAbstract:The eye and the brain are immunologically privileged sites, a property previously attributed to the lack of a lymphatic circulation. However, recent tracking studies confirm that these organs have good communication through classical site-specific lymph nodes, as well as direct connection through the blood circulation with the spleen. In addition, like all tissues, they contain resident myeloid cell populations that play important roles in tissue homeostasis and the response to foreign antigens. Most of the macrophage and dendritic cell (DC) populations in the eye are restricted to the supporting connective tissues, including the cornea, while the neural tissue (the retina) contains almost no DCs, occasional macrophages (perivascularly distributed), and a specialized myeloid cell type, the microglial cell. Resident microglial cells are normally programmed for immunological tolerance. The privileged status of the eye, however, is relative, as it is susceptible to immune-mediated inflammatory disease, both infectious and autoimmune. Intraocular inflammation (uveitis and Uveoretinitis) and corneal graft rejection constitute two of the more common inflammatory conditions affecting the eye leading to considerable morbidity (blindness). As corneal graft rejection occurs almost exclusively by indirect allorecognition, host DCs play a major role in this process and are likely to be modified in their behavior by the ocular microenvironment. Ocular surface disease, including allergy and atopy, also comprise a significant group of immune-mediated eye disorders in which DCs participate, while infectious disease such as herpes simplex keratitis is thought to be initiated via corneal DCs. Intriguingly, some more common conditions previously thought to be degenerative (e.g. age-related macular degeneration) may have an autoimmune component in which ocular DCs and macrophages are critically involved. Recently, the possibility of harnessing the tolerizing potential of DCs has been applied to experimental models of autoimmune Uveoretinitis with good effect. This approach has considerable potential for use in translational clinical therapy to prevent sight-threatening disease caused by ocular inflammation.
Lindsay B. Nicholson - One of the best experts on this subject based on the ideXlab platform.
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The B subunit of Escherichia coli heat-labile enterotoxin inhibits Th1 but not Th17 cell responses in established experimental autoimmune Uveoretinitis
2013Co-Authors: Ben J. E. Raveney, Marie-laure Aknin, Bronwen R. Burton, Lindsay B. Nicholson, Neil A. Williams, David A. Copl, Claire Richards, Emma Kerr, Andrew D DickAbstract:PURPOSE. To investigate the efficacy of the B subunit of Escherichia coli heat-labile enterotoxin (EtxB) in the treatment of ocular autoimmune disease. Murine experimental autoimmune Uveoretinitis (EAU) is an animal model of autoimmune posterior uveitis initiated by retinal antigen-specific Th1 and Th17 CD4 � T cells, which activate myeloid cells, inducing retinal damage. EtxB is a potent immune modulator that ameliorates other Th1-mediated autoimmune diseases, enhancing regulatory T-cell activity. METHODS. EAU was induced in B10.RIII mice by immunization with peptide hIRBP 161-180. Disease severity was measured by clinical and histologic assessment, and functional responses of macrophages (M�s) and T cells were assessed, both in vivo and in cocultures in vitro. EtxB was administered intranasally daily for 4 days, starting either 3 days before or 3 days after EA
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The Journal of Immunology A Selective Role for the TNF p55 Receptor in Autocrine Signaling following IFN- � Stimulation in Experimental
2013Co-Authors: Autoimmune Uveoretinitis, Lindsay B. Nicholson, Claudia J. Calder, Andrew D DickAbstract:IFN- � stimulates macrophage activation and NO production, which leads to destruction of the retina in experimental autoimmune Uveoretinitis. In this study, we investigate the mechanism of disease resistance in TNF p55 receptor-deficient animals. We show that although T cell priming is relatively unaffected, macrophages lacking the TNF p55 receptor fail to produce NO following IFN- � stimulation because of a requirement for autocrine TNF- � signaling through the TNF p55 receptor. In contrast to the impaired activation of NO synthesis, MHC class II up-regulation was indistinguishable in wild-type and TNFRp55 �/ � mice stimulated with IFN-�. These defects could be overcome by stimulating macrophages with LPS. Together, these results show that selected aspects of IFN- � activation are controlled by autocrine secretion of TNF-�, but that this control is lost in the presence of signals generated by pathogen-associated molecular patterns recognizing receptors. The Journal of Immunology, 2005, 175: 6286–6293. Studies of experimental autoimmune Uveoretinitis (EAU) 3 have provided abundant evidence that TNF- � plays a pivotal role in the pathogenesis of intraocular inflammation and retinal tissue destruction. EAU is an organ-specific autoimmune disease in which Th1 CD4 � T cells, directed toward retinal Ags, produce cytokines, such as IFN-�, which activate residen
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The Clinical Time-Course of Experimental Autoimmune Uveoretinitis Using Topical Endoscopic Fundal Imaging with Histologic and Cellular Infiltrate Correlation
2013Co-Authors: David A. Copl, Ben J. E. Raveney, Lindsay B. Nicholson, Michael S. Wertheim, John W. Armitage, Andrew D DickAbstract:PURPOSE. EAU is an established preclinical model for assessment of immunotherapeutic efficacy toward translation of therapy for posterior uveitis. Reliable screening of clinical features that correlate with underlying retinal changes and damage has not been possible to date. This study was undertaken to describe, validate, and correlate topical endoscopic fundus imaging (TEFI) with histologic features of murine experimental autoimmune Uveoretinitis (EAU), with the intent of generating a rapid noninvasive panretinal assessment of ocular inflammation. METHODS. EAU was induced in B10.RIII mice by immunization with the peptide RBP-3161-180. The clinical disease course (days 0–63) was monitored and documented using TEFI. Disease severity and pathology were confirmed at various time points by histologic assessment. The composition of the cell infiltrate was also examined and enumerated by flow cytometry
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tnfr1 dependent regulation of myeloid cell function in experimental autoimmune Uveoretinitis
Journal of Immunology, 2009Co-Authors: Ben J. E. Raveney, Andrew D Dick, David A. Copland, Lindsay B. NicholsonAbstract:Experimental autoimmune Uveoretinitis is an autoimmune disease induced in mice, which involves the infiltration of CD11b + macrophages and CD4 + T cells into the normally immune-privileged retina. Damage is produced in the target organ following the activation of Th1 and Th17 T cells and by the release of cytotoxic mediators such as NO by activated macrophages. The majority of immune cells infiltrating into the retina are CD11b + myeloid cells, but, despite the presence of these APCs, relatively limited numbers of T cells are observed in the retina during the disease course. These T cells do not proliferate when leukocytes are isolated from the retina and restimulated in vitro, although they do produce both IFN-γ and IL-17. T cell proliferation was restored by depleting the myeloid cells from the cultures and furthermore those isolated myeloid cells were able to regulate the proliferation of other T cells. The ability of macrophages to regulate proliferation depends on activation by T cell-produced IFN-γ and autocrine TNF-α signaling in the myeloid cells via TNFR1. In the absence of TNFR1 signaling, relative T cell expansion in the retina is increased, indicating that regulatory myeloid cells may also act in vivo. However, TNFR1 signaling is also required for macrophages, but not T cells, to migrate into the target organ. Thus, in TNFR1 knock out mice, the amplification of autoimmunity is limited, leading to resistance to experimental autoimmune Uveoretinitis induction.
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the dynamics of leukocyte infiltration in experimental autoimmune Uveoretinitis
Progress in Retinal and Eye Research, 2008Co-Authors: Emma C. Kerr, Andrew D Dick, David A. Copland, Lindsay B. NicholsonAbstract:Experimental autoimmune Uveoretinitis (EAU) serves as an animal model for human uveitis. EAU is inducible in animals by peripheral immunization with proteins found in the retina that triggers an immune response which leads to tissue damage. This is coordinated by autoantigen specific CD4 T cells whose activation is accompanied by the infiltration of a wide range of other leukocytes into the retina. Infiltrating macrophages and granulocytes cause destruction by the release of reactive oxygen and nitrogen species but these and other leukocytes also regulate inflammation. This review will describe the dynamics of leukocyte infiltration in EAU from the initial systemic activation of T cells following immunization, through their traffic into the eye causing a peak of infiltration, and ending with a phase of secondary regulation in which, although clinical disease has resolved, the leukocyte composition of the eye remains altered.
Ben J. E. Raveney - One of the best experts on this subject based on the ideXlab platform.
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The B subunit of Escherichia coli heat-labile enterotoxin inhibits Th1 but not Th17 cell responses in established experimental autoimmune Uveoretinitis
2013Co-Authors: Ben J. E. Raveney, Marie-laure Aknin, Bronwen R. Burton, Lindsay B. Nicholson, Neil A. Williams, David A. Copl, Claire Richards, Emma Kerr, Andrew D DickAbstract:PURPOSE. To investigate the efficacy of the B subunit of Escherichia coli heat-labile enterotoxin (EtxB) in the treatment of ocular autoimmune disease. Murine experimental autoimmune Uveoretinitis (EAU) is an animal model of autoimmune posterior uveitis initiated by retinal antigen-specific Th1 and Th17 CD4 � T cells, which activate myeloid cells, inducing retinal damage. EtxB is a potent immune modulator that ameliorates other Th1-mediated autoimmune diseases, enhancing regulatory T-cell activity. METHODS. EAU was induced in B10.RIII mice by immunization with peptide hIRBP 161-180. Disease severity was measured by clinical and histologic assessment, and functional responses of macrophages (M�s) and T cells were assessed, both in vivo and in cocultures in vitro. EtxB was administered intranasally daily for 4 days, starting either 3 days before or 3 days after EA
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The Clinical Time-Course of Experimental Autoimmune Uveoretinitis Using Topical Endoscopic Fundal Imaging with Histologic and Cellular Infiltrate Correlation
2013Co-Authors: David A. Copl, Ben J. E. Raveney, Lindsay B. Nicholson, Michael S. Wertheim, John W. Armitage, Andrew D DickAbstract:PURPOSE. EAU is an established preclinical model for assessment of immunotherapeutic efficacy toward translation of therapy for posterior uveitis. Reliable screening of clinical features that correlate with underlying retinal changes and damage has not been possible to date. This study was undertaken to describe, validate, and correlate topical endoscopic fundus imaging (TEFI) with histologic features of murine experimental autoimmune Uveoretinitis (EAU), with the intent of generating a rapid noninvasive panretinal assessment of ocular inflammation. METHODS. EAU was induced in B10.RIII mice by immunization with the peptide RBP-3161-180. The clinical disease course (days 0–63) was monitored and documented using TEFI. Disease severity and pathology were confirmed at various time points by histologic assessment. The composition of the cell infiltrate was also examined and enumerated by flow cytometry
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tnfr1 dependent regulation of myeloid cell function in experimental autoimmune Uveoretinitis
Journal of Immunology, 2009Co-Authors: Ben J. E. Raveney, Andrew D Dick, David A. Copland, Lindsay B. NicholsonAbstract:Experimental autoimmune Uveoretinitis is an autoimmune disease induced in mice, which involves the infiltration of CD11b + macrophages and CD4 + T cells into the normally immune-privileged retina. Damage is produced in the target organ following the activation of Th1 and Th17 T cells and by the release of cytotoxic mediators such as NO by activated macrophages. The majority of immune cells infiltrating into the retina are CD11b + myeloid cells, but, despite the presence of these APCs, relatively limited numbers of T cells are observed in the retina during the disease course. These T cells do not proliferate when leukocytes are isolated from the retina and restimulated in vitro, although they do produce both IFN-γ and IL-17. T cell proliferation was restored by depleting the myeloid cells from the cultures and furthermore those isolated myeloid cells were able to regulate the proliferation of other T cells. The ability of macrophages to regulate proliferation depends on activation by T cell-produced IFN-γ and autocrine TNF-α signaling in the myeloid cells via TNFR1. In the absence of TNFR1 signaling, relative T cell expansion in the retina is increased, indicating that regulatory myeloid cells may also act in vivo. However, TNFR1 signaling is also required for macrophages, but not T cells, to migrate into the target organ. Thus, in TNFR1 knock out mice, the amplification of autoimmunity is limited, leading to resistance to experimental autoimmune Uveoretinitis induction.
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The B subunit of Escherichia coli heat-labile enterotoxin inhibits Th1 but not Th17 cell responses in established experimental autoimmune Uveoretinitis.
Investigative ophthalmology & visual science, 2008Co-Authors: Ben J. E. Raveney, David A. Copland, C. M. Richards, Marie-laure Aknin, Bronwen R. Burton, Emma C. Kerr, Lindsay B. Nicholson, Neil A. Williams, Andrew D DickAbstract:PURPOSE. To investigate the efficacy of the B subunit of Escherichia coli heat-labile enterotoxin (EtxB) in the treatment of ocular autoimmune disease. Murine experimental autoimmune Uveoretinitis (EAU) is an animal model of autoimmune posterior uveitis initiated by retinal antigen-specific Th1 and Th17 CD4 T cells, which activate myeloid cells, inducing retinal damage. EtxB is a potent immune modulator that ameliorates other Th1-mediated autoimmune diseases, enhancing regulatory T-cell activity.
Rachel R. Caspi - One of the best experts on this subject based on the ideXlab platform.
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Running Title: Correspondence to: Immune mechanims in uveitis
2015Co-Authors: Rachel R. Caspi, Ph. DAbstract:Caspi, Immune mechanims in uveitis p. 2 EAU as a model of human uveitis Experimental autoimmune Uveoretinitis (EAU) is an animal model of posterior uveitic diseases in the human. EAU can be induced in susceptible animal species by immunization with retinal antigens or their fragments, and in mice and rats also by infusion of T cells specific to these antigens, that are isolated from immunized animals and cultured for various periods of time in the laboratory. Susceptible animal species include rodents as well as primates, which makes this model useful not only for basic studies of immune mechanisms but also for preclinical testing of therapeutic modalities [1-3]. A number of antigens that induce Uveoretinitis in laboratory animals have been identified over the years, using as starting material bovine retinal extracts. Subsequently, the genes for these antigens were cloned from a variety of animal species and characterized. Typically, uveitogenic antigens tend to represent evolutionarily conserved proteins involved in one way or another in visual functioning. They include the retinal soluble antigen (S-Ag): a 48 kilodalton intracellular protein that participates in phototransduction; the interphotoreceptor retinoid-binding bindin
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Rodent Models of Experimental Autoimmune Uveitis
2015Co-Authors: Andras Perl, Rajeev K. Agarwal, Rachel R. CaspiAbstract:The model of experimental autoimmune uveitis (EAU) in mice and in rats is described. EAU targets immunologically privileged retinal antigens and serves as a model of autoimmune uveitis in humans as well as a model for autoimmunity in a more general sense. EAU is a well-characterized, robust, and reproducible model that is easily followed and quantitated. It is induc-ible with synthetic peptides derived from retinal autoantigens in commonly available strains of rats and mice. The ability to induce EAU in various gene-manipulated, including HLA-transgenic, mouse strains makes the EAU model suitable for the study of basic mechanisms as well as in clinically relevant interventions. Key Words: Autoimmunity; EAU; IRBP; S-Ag; T cells; Th1; Th2; tolerance; uveitis; Uveoretinitis
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experimental autoimmune Uveoretinitis in the rat and mouse
Current protocols in immunology, 2003Co-Authors: Rachel R. CaspiAbstract:Experimental autoimmune Uveoretinitis (EAU) in rats and mice is a prototypic T cell-mediated autoimmune disease that targets the neural retina and related tissues. The model is used to represent human sight-threatening inflammatory eye diseases that are believed to have an autoimmune etiology, and to study basic mechanisms of tolerance and autoimmunity to organ-specific antigens from immunologically privileged sites. In this unit, EAU is induced in rats and mice by immunization with uveitogenic peptide antigens emulsified in complete Freund's adjuvant (CFA). Clinical onset is observed by both external and microscopic examination. A protocol is provided for preparation of tissue sections of affected eyes for microscopic analysis. EAU can also be induced in the rat (as described) by adoptive transfer of lymphocytes from uveitic rats into unimmunized recipients, which obviates the use of CFA. To induce EAU in mice, Bordetella pertussis toxin (PTX) is included to overcome immunological resistance mechanisms.
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fas fas ligand associated apoptosis in experimental autoimmune Uveoretinitis in rodents role of proinflammatory corticotropin releasing hormone
Experimental Eye Research, 2001Co-Authors: Vassiliki Poulaki, Rachel R. Caspi, Nicholas Mitsiades, George Mastorakos, George P Chrousos, Evrydiki A BouzasAbstract:We have previously shown that corticotropin-releasing hormone plays an important proinflammatory role in the induction of experimental autoimmune Uveoretinitis. In this study, we examined the role of apoptosis in the destruction of the retina during experimental autoimmune Uveoretinitis, and the role of corticotropin-releasing hormone as a local regulator of Fas and Fas Ligand expression in this condition. We evaluated apoptosis by the terminal deoxynucleotidyl transferase dUTP nick end labeling method and Fas and Fas Ligand presence by immunohistochemistry. We examined formalin-fixed, paraffin-embedded eye sections from female Lewis rats or B10.A mice immunized with the major pathogenetic epitope (R16 peptide) of the interphotoreceptor retinoid-binding protein. Female B10.A mice similarly immunized were treated with intraperitoneal injections of the rabbit anti-corticotropin-releasing hormone antibody TS-2 or nonimmune rabbit serum. The percentage of retinal cells undergoing apoptosis and the expression of Fas and Fas Ligand were increased in inflamed retinas in immunized Lewis rats and B10.A mice, compared to controls. Retinas from immunized B10.A mice treated with anti-corticotropin-releasing hormone antibody showed significantly lower apoptosis and Fas and Fas Ligand expression than placebo-treated animals. In conclusion, retinal cells in experimental autoimmune Uveoretinitis undergo apoptosis associated with concurrent upregulation of Fas and Fas Ligand. The local presence of corticotropin-releasing hormone appears to be of pivotal importance in this process.
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IL-10 has a protective role in experimental autoimmune Uveoretinitis.
International immunology, 1998Co-Authors: Luiz Vicente Rizzo, Chi-chao Chan, Barbara Wiggert, Rachel R. CaspiAbstract:The role of IL-10 in the regulation of ocular autoimmune disease was studied in experimental autoimmune Uveoretinitis (EAU) elicited in mice by immunization with the retinal antigen interphotoreceptor retinoid binding protein. IL-10-deficient mice were susceptible to EAU, indicating that pathogenesis can occur without presence of IL-10. Treatment of normal mice with IL-10 for 5 days after uveitogenic immunization ameliorated subsequent EAU scores, and down-regulated antigen-specific production of tumor necrosis factor-alpha and IFN-gamma. A concomitant treatment with IL-4 further reduced disease, and resulted in emergence of antigen-specific IL-4 and IL-10 production, as well as in enhancement of the IgG1 antibody isotype. IL-4 by itself was not protective. Only IL-10, but not IL-4, was able to inhibit the function of differentiated uveitogenic T cells in culture. Expression of mRNA for Th1 and Th2 cytokines in the eye during the course of EAU showed that while a Th1 pattern predominated early, IL-10 mRNA expression coincided with down-regulation of the Th1 response and resolution of EAU. Systemic neutralization of IL-10 during the expression phase of EAU resulted in elevated disease scores. Our results suggest that endogenous IL-10 limits expression of EAU and may play a role in the natural resolution of disease. The data further suggest that exogenous IL-10 may be useful in therapeutic control of autoimmune uveitis. While IL-10 by itself is sufficient to suppress Th1 effector development and function, a concomitant administration of IL-4 is required to shift the autoimmune response towards a non-pathogenic Th2 pathway.
Chi-chao Chan - One of the best experts on this subject based on the ideXlab platform.
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Effect of sex hormones on experimental autoimmune Uveoretinitis (EAU).
Immunological investigations, 2003Co-Authors: Ronald Buggage, Dawn M. Matteson, De Fen Shen, Bing Sun, Nadine Tuaillon, Chi-chao ChanAbstract:Purpose: Sex hormones have been associated with the prevalence, susceptibility, and severity of autoimmune disease. Although the exact mechanism is unknown, sex hormones are reported to influence cytokine production, specifically by affecting the balance of Th1 and Th2 effector cells. We evaluated the effect of estrogen, progesterone, and testosterone in autoimmune Uveoretinitis (EAU), a rodent model of human ocular autoimmune disease. Methods: Lewis rats implanted with either β‐estradiol (estrogen), 5‐dihydrotestosterone (5‐DHT), norgestrel (progesterone), or estrogen plus progesterone were immunized with the retinal antigen interphotoreceptor retinoid binding protein (IRBP) peptide. Evaluation of EAU was based on histology of the eyes and measurement of peripheral immunological responses of DTH and lymphocyte proliferation to S‐antigen. Quantitative RT‐PCR was used to measure IFN‐γ and IL‐10 mRNA in the eyes. Results: In female rats 5‐DHT significantly decreased, estrogen slightly enhanced, but progeste...
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copolymer 1 inhibits experimental autoimmune Uveoretinitis
Journal of Neuroimmunology, 2000Co-Authors: Meifen Zhang, Barbara P Vistica, Chi-chao Chan, Barbara Wiggert, Vivian Hung, Igal GeryAbstract:Abstract Copolymer 1 (Cop 1) inhibits experimental allergic encephalomyelitis induced by a variety of myelin proteins, but has been found ineffective so far in inhibiting other experimental autoimmune diseases such as diabetes or arthritis. Here, we report for the first time that Cop 1 inhibits the development of experimental autoimmune Uveoretinitis, induced in mice by interphotoreceptor retinoid-binding protein (IRBP). Pooled data of three experiments showed that treatment with Cop 1, at 0.5 mg/mouse, reduced the disease severity by 53% ( p =0.0002). Cop 1 treatment also inhibited the proliferation and the production of cytokines by lymph node cells in response to IRBP and moderately reduced the antibody response to this antigen. The possible mechanisms of EAU inhibition by Cop 1 are discussed.
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IL-10 has a protective role in experimental autoimmune Uveoretinitis.
International immunology, 1998Co-Authors: Luiz Vicente Rizzo, Chi-chao Chan, Barbara Wiggert, Rachel R. CaspiAbstract:The role of IL-10 in the regulation of ocular autoimmune disease was studied in experimental autoimmune Uveoretinitis (EAU) elicited in mice by immunization with the retinal antigen interphotoreceptor retinoid binding protein. IL-10-deficient mice were susceptible to EAU, indicating that pathogenesis can occur without presence of IL-10. Treatment of normal mice with IL-10 for 5 days after uveitogenic immunization ameliorated subsequent EAU scores, and down-regulated antigen-specific production of tumor necrosis factor-alpha and IFN-gamma. A concomitant treatment with IL-4 further reduced disease, and resulted in emergence of antigen-specific IL-4 and IL-10 production, as well as in enhancement of the IgG1 antibody isotype. IL-4 by itself was not protective. Only IL-10, but not IL-4, was able to inhibit the function of differentiated uveitogenic T cells in culture. Expression of mRNA for Th1 and Th2 cytokines in the eye during the course of EAU showed that while a Th1 pattern predominated early, IL-10 mRNA expression coincided with down-regulation of the Th1 response and resolution of EAU. Systemic neutralization of IL-10 during the expression phase of EAU resulted in elevated disease scores. Our results suggest that endogenous IL-10 limits expression of EAU and may play a role in the natural resolution of disease. The data further suggest that exogenous IL-10 may be useful in therapeutic control of autoimmune uveitis. While IL-10 by itself is sufficient to suppress Th1 effector development and function, a concomitant administration of IL-4 is required to shift the autoimmune response towards a non-pathogenic Th2 pathway.
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humanized antibodies against the alpha chain of the il 2 receptor and against the beta chain shared by the il 2 and il 15 receptors in a monkey uveitis model of autoimmune diseases
Journal of Immunology, 1997Co-Authors: Y Guexcrosier, Chi-chao Chan, J Raber, M S Kriete, J Benichou, R S Pilson, J A Kerwin, Thomas A Waldmann, J Hakimi, Francois G RobergeAbstract:We studied the efficacy and tolerance of humanized Ab interfering with the signal of the IL-2 and IL-15 receptors in a primate model of experimental autoimmune Uveoretinitis. The inhibitory effects of humanized anti-Tac (HAT), an anti-IL-2R alpha-chain Ab, and HuMik beta1, an Ab directed at the beta-chain shared by the receptors of IL-2 and IL-15, were tested in culture on the proliferative response of monkey Con A-blast lymphocytes stimulated with IL-2 or IL-15. Uveitis was induced in cynomolgus monkeys by immunization with human recombinant retinal S-antigen. Treatment was initiated at the first sign of disease and consisted of HAT and HuMik beta1, alone or in combination, or vehicle control given by i.v. injection twice a week for 4 wk. Disease was evaluated by ocular funduscopy. The results in culture showed a significant dose-dependent inhibition of the IL-2-driven proliferation of lymphocytes by HAT. HuMik beta1 alone was ineffective against IL-2 stimulation, but had a marked potentiating effect in combination with HAT, independent of IL-15 signaling. IL-15-driven proliferation was inhibited by HuMik beta1, but not by HAT alone or in combination. In monkeys, experimental autoimmune Uveoretinitis evolution was significantly inhibited by HAT treatment. HuMik beta1 alone had no effect on the disease. However, when used in combination, the two Ab markedly reduced the severity of ocular inflammation. The Ab were well tolerated. Only three monkeys, treated with HAT alone, made an Ab response against the injected Ab.
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anti tumor necrosis factor alpha therapy suppresses the induction of experimental autoimmune Uveoretinitis in mice by inhibiting antigen priming
Investigative Ophthalmology & Visual Science, 1996Co-Authors: Gil Sartani, Luiz Vicente Rizzo, Chi-chao Chan, Barbara Wiggert, George Mastorakos, Phyllis B Silver, Rachel R. CaspiAbstract:Purpose. Experimental autoimmune Uveoretinitis (EAU) serves as a model for several immunemediated diseases that affect the eye in humans. Previous studies indicated that tumor necrosis factor alpha (TNF-a) has an important proinflammatory role in EAU and possibly in human uveitis. In this study, the authors investigated the effect of anti-TNF-a therapy on EAU in mice. Methods. Experimental autoimmune Uveoretinitis was induced in B10.A mice by immunization with interphotoreceptor retinoid-binding protein (IRBP). The mice were treated with 100 or 300 pi rabbit antiserum or polyclonal antibodies to human TNF-a. The treatment spanned either the afferent or the efferent stage of EAU (days —1, 1, 3, 5, 7, or days 8, 10, 12, 14, 16, respectively). Control animals were injected with preimmune rabbit serum at the corresponding times or were not treated. Three weeks after immunization, EAU was assessed by clinical evaluation and by histopathology. Immunologic responses were assessed by delayed-type hypersensitivity (DTH), lymphocyte proliferation to IRBP, and relative abundance of IRBP-primed splenocytes. Results. The treatment widi rabbit anti-TNF-a serum significandy ameliorated disease when given during the afferent stage but had no effect when given during die efferent stage of EAU. The effect on DTH, lymphocyte proliferation, and abundance of antigen-reactive cells roughly paralleled the effect on disease. Conclusions. Neutralization of systemic TNF ameliorates EAU. The effectiveness of afferent treatment in comparison to die treatment during die efferent stage, together with the reduced proliferation and the reduced abundance of IRBP-responsive cells, suggest that interference with afferent-acting processes such as antigen priming is important to achieve protection from EAU by anti-TNF treatment. Invest Ophthalmol Vis Sci. 1996;37:2211-2218.
