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Rachel R. Caspi - One of the best experts on this subject based on the ideXlab platform.
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AS101 ameliorates experimental Autoimmune Uveitis by regulating Th1 and Th17 responses and inducing Treg cells
Journal of autoimmunity, 2019Co-Authors: So Jin Bing, Phyllis B. Silver, Reiko Horai, Itay Israel Shemesh, Wai Po Chong, Yingyos Jittayasothorn, Benjamin Sredni, Rachel R. CaspiAbstract:AS101 is an organotellurium compound with multifaceted immunoregulatory properties that is remarkable for its lack of toxicity. We tested the therapeutic effect of AS101 in experimental Autoimmune Uveitis (EAU), a model for human Autoimmune Uveitis. Unexpectedly, treatment with AS101 elicited Treg generation in vivo in otherwise unmanipulated mice. Mice immunized for EAU with the retinal antigen IRBP and treated with AS101 developed attenuated disease, as did AS101-treated recipients of retina-specific T cells activated in vitro. In both settings, eye-infiltrating effector T cells were decreased, whereas regulatory T (Treg) cells in the spleen were increased. Mechanistic studies in vitro revealed that AS101 restricted polarization of retina-specific T cells towards Th1 or Th17 lineage by repressing activation of their respective lineage-specific transcription factors and downstream signals. Retina-specific T cells polarized in vitro towards Th1 or Th17 in the presence of AS101 had impaired ability to induce EAU in naive recipients. Finally, AS101 promoted differentiation of retina-specific T cells to Tregs in vitro independently of TGF-β. We conclude that AS101 modulates Autoimmune T cells by inhibiting acquisition and expression of effector function and by promoting Treg generation, and suggest that AS101 could be useful as a therapeutic approach for Autoimmune Uveitis.
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Targeting CD6 for the treatment of experimental Autoimmune Uveitis.
Journal of autoimmunity, 2018Co-Authors: Lingjun Zhang, Rachel R. Caspi, Brent A. Bell, Wen Qiu, Nina Dvorina, William M. Baldwin, Nora G. Singer, Timothy S. Kern, David A. FoxAbstract:Abstract Objective CD6 is emerging as a new target for treating many pathological conditions in which T cells are integrally involved, but even the latest data from studies of CD6 gene engineered mice were still contradictory. To address this issue, we studied experimental Autoimmune Uveitis (EAU), a model of Autoimmune Uveitis, in wild-type (WT) and CD6 knockout (KO) mice. Methods After EAU induction in WT and CD6 KO mice, we evaluated ocular inflammation and compared retinal antigen-specific T-cell responses using scanning laser ophthalmoscopy, spectral-domain optical coherence tomography, histopathology, and T cell recall assays. Uveitogenic T cells from WT and CD6 KO mice were adoptively transferred into WT naive mice to confirm the impact of CD6 on T cells. In addition, we immunized CD6 KO mice with recombinant CD6 protein to develop mouse anti-mouse CD6 monoclonal antibodies (mAbs) in which functional antibodies exhibiting cross-reactivity with human CD6 were screened and identified for treatment studies. Results In CD6 KO mice with EAU, we found significantly decreased retinal inflammation and reduced autoreactive T-cell responses, and confirmed the impaired uveitogenic capacity of T cells from these mice in an adoptive transfer experiment. Notably, one of these cross-reactive mAbs significantly ameliorated retinal inflammation in EAU induced by the adoptive transfer of uveitogenic T cells. Conclusions Together, these data strongly suggest that CD6 plays a previously unknown, but pivotal role in Autoimmune Uveitis, and may be a promising new treatment target for this blinding disease. In addition, the newly developed mouse anti-mouse/human CD6 mAbs could be valuable tools for testing CD6-targeted therapies in other mouse models of human diseases.
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Animal Models of Autoimmune Uveitis
Animal Models of Ophthalmic Diseases, 2015Co-Authors: Jennifer L. Kielczewski, Rachel R. CaspiAbstract:There are several animal models that have proved useful in understanding the mechanisms and pathogenesis of Uveitis. One of the oldest animal models of Uveitis widely used is experimental Autoimmune Uveitis (EAU, Agarwal and Caspi). It can be induced by either injection of specific photoreceptor proteins, such as arrestin (S-antigen) or interphotoreceptor retinoid-binding protein (IRBP), or other retinal proteins like melanin. There are also spontaneous models of Uveitis, as well as genetically “humanized” models that have been recently developed. This chapter describes and discusses these major experimental animal models of Uveitis—both old and new—with emphasis on their advantages and disadvantages in translational ophthalmic research.
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Complement anaphylatoxin receptors C3aR and C5aR are required in the pathogenesis of experimental Autoimmune Uveitis.
Journal of leukocyte biology, 2015Co-Authors: Lingjun Zhang, Rachel R. Caspi, Chi-chao Chan, Brent A. Bell, Neal S. Peachey, John J. Fung, Xiaoming Zhang, Feng LinAbstract:Recent studies have suggested that reagents inhibiting complement activation could be effective in treating T cell mediated Autoimmune diseases such as Autoimmune Uveitis. However, the precise role of the complement anaphylatoxin receptors (C3a and C5a receptors) in the pathogenesis of Autoimmune Uveitis remains elusive and controversial. We induced experimental Autoimmune Uveitis in mice deficient or sufficient in both C3a and C5a receptors and rigorously compared their retinal phenotype using various imaging techniques, including indirect ophthalmoscopy, confocal scanning laser ophthalmoscopy, spectral domain optical coherence tomography, topical endoscopic fundus imaging, and histopathological analysis. We also assessed retinal function using electroretinography. Moreover, we performed Ag-specific T cell recall assays and T cell adoptive transfer experiments to compare pathogenic T cell activity between wild-type and knockout mice with experimental Autoimmune Uveitis. These experiments showed that C3a receptor/C5a receptor-deficient mice developed much less severe Uveitis than did control mice using all retinal examination methods and that these mice had reduced pathogenic T cell responses. Our data demonstrate that both complement anaphylatoxin receptors are important for the development of experimental Autoimmune Uveitis, suggesting that targeting these receptors could be a valid approach for treating patients with Autoimmune Uveitis.
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retina specific t regulatory cells bring about resolution and maintain remission of Autoimmune Uveitis
Journal of Immunology, 2015Co-Authors: Phyllis B. Silver, Chi-chao Chan, Reiko Horai, Yingyos Jittayasothorn, Jun Chen, Rafael Villasmil, Muge R Kesen, Rachel R. CaspiAbstract:Experimental Autoimmune Uveitis (EAU) induced in mice by immunization with the retinal Ag interphotoreceptor retinoid-binding protein (IRBP) is a model of human Autoimmune Uveitis. We examined whether T regulatory cells (Tregs) found in uveitic eyes are IRBP specific, functionally suppressive, and play a role in natural resolution of disease and in maintenance of remission. Progressive increase of Foxp3(+) Treg to T effector cell (Teff) ratio in uveitic eyes correlated with resolution of disease. At peak disease, up to 20% of Tregs (CD4(+)Foxp3(+)) and up to 60% of Teffs (CD4(+)Foxp3(-)) were IRBP specific, whereas in lymphoid organs retina-specific T cells were undetectable. Tregs isolated from eyes of mice with EAU efficiently suppressed IRBP-specific responses of Teffs from the same eyes. Importantly, systemic depletion of Tregs at peak disease delayed resolution of EAU, and their depletion after resolution triggered a relapse. This could be partially duplicated by depletion of Tregs locally within the eye. Thus, the T cell infiltrate in uveitic eyes of normal mice with a polyclonal T cell repertoire is highly enriched in IRBP-specific Tregs and Teffs. Unlike what has been reported for Tregs in other inflammatory sites, Tregs from uveitic eyes appear unimpaired functionally. Finally, Foxp3(+) Tregs play a role in the natural resolution of Uveitis and in the maintenance of remission, which occurs at least in part through an effect that is local to the eye.
Lingjun Zhang - One of the best experts on this subject based on the ideXlab platform.
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Targeting CD6 for the treatment of experimental Autoimmune Uveitis.
Journal of autoimmunity, 2018Co-Authors: Lingjun Zhang, Rachel R. Caspi, Brent A. Bell, Wen Qiu, Nina Dvorina, William M. Baldwin, Nora G. Singer, Timothy S. Kern, David A. FoxAbstract:Abstract Objective CD6 is emerging as a new target for treating many pathological conditions in which T cells are integrally involved, but even the latest data from studies of CD6 gene engineered mice were still contradictory. To address this issue, we studied experimental Autoimmune Uveitis (EAU), a model of Autoimmune Uveitis, in wild-type (WT) and CD6 knockout (KO) mice. Methods After EAU induction in WT and CD6 KO mice, we evaluated ocular inflammation and compared retinal antigen-specific T-cell responses using scanning laser ophthalmoscopy, spectral-domain optical coherence tomography, histopathology, and T cell recall assays. Uveitogenic T cells from WT and CD6 KO mice were adoptively transferred into WT naive mice to confirm the impact of CD6 on T cells. In addition, we immunized CD6 KO mice with recombinant CD6 protein to develop mouse anti-mouse CD6 monoclonal antibodies (mAbs) in which functional antibodies exhibiting cross-reactivity with human CD6 were screened and identified for treatment studies. Results In CD6 KO mice with EAU, we found significantly decreased retinal inflammation and reduced autoreactive T-cell responses, and confirmed the impaired uveitogenic capacity of T cells from these mice in an adoptive transfer experiment. Notably, one of these cross-reactive mAbs significantly ameliorated retinal inflammation in EAU induced by the adoptive transfer of uveitogenic T cells. Conclusions Together, these data strongly suggest that CD6 plays a previously unknown, but pivotal role in Autoimmune Uveitis, and may be a promising new treatment target for this blinding disease. In addition, the newly developed mouse anti-mouse/human CD6 mAbs could be valuable tools for testing CD6-targeted therapies in other mouse models of human diseases.
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Therapeutic effects of mesenchymal stem cells administered at later phase of recurrent experimental Autoimmune Uveitis.
International journal of ophthalmology, 2016Co-Authors: Ping-ting Zhao, Lingjun Zhang, Hui Shao, Lingling Bai, Lijie Dong, Xun Liu, Xiaomin ZhangAbstract:AIM To test the therapeutic effects of delayed treatment of mesenchymal stem cells (MSCs) in recurrent experimental Autoimmune Uveitis (rEAU).
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Complement anaphylatoxin receptors C3aR and C5aR are required in the pathogenesis of experimental Autoimmune Uveitis.
Journal of leukocyte biology, 2015Co-Authors: Lingjun Zhang, Rachel R. Caspi, Chi-chao Chan, Brent A. Bell, Neal S. Peachey, John J. Fung, Xiaoming Zhang, Feng LinAbstract:Recent studies have suggested that reagents inhibiting complement activation could be effective in treating T cell mediated Autoimmune diseases such as Autoimmune Uveitis. However, the precise role of the complement anaphylatoxin receptors (C3a and C5a receptors) in the pathogenesis of Autoimmune Uveitis remains elusive and controversial. We induced experimental Autoimmune Uveitis in mice deficient or sufficient in both C3a and C5a receptors and rigorously compared their retinal phenotype using various imaging techniques, including indirect ophthalmoscopy, confocal scanning laser ophthalmoscopy, spectral domain optical coherence tomography, topical endoscopic fundus imaging, and histopathological analysis. We also assessed retinal function using electroretinography. Moreover, we performed Ag-specific T cell recall assays and T cell adoptive transfer experiments to compare pathogenic T cell activity between wild-type and knockout mice with experimental Autoimmune Uveitis. These experiments showed that C3a receptor/C5a receptor-deficient mice developed much less severe Uveitis than did control mice using all retinal examination methods and that these mice had reduced pathogenic T cell responses. Our data demonstrate that both complement anaphylatoxin receptors are important for the development of experimental Autoimmune Uveitis, suggesting that targeting these receptors could be a valid approach for treating patients with Autoimmune Uveitis.
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Long-term therapeutic effects of mesenchymal stem cells compared to dexamethasone on recurrent experimental Autoimmune Uveitis of rats.
Investigative ophthalmology & visual science, 2014Co-Authors: Lingjun Zhang, Hui Shao, Lingling Bai, Xun Liu, Hong Nian, Hui Zheng, Yan Zhang, Lijie DongAbstract:Purpose. We tested the long-term effects of different regimens of mesenchymal stem cell (MSC) administration in a recurrent experimental Autoimmune Uveitis (rEAU) model in rats, and compared the efficacy of MSC to that of dexamethasone (DEX).
Chi-chao Chan - One of the best experts on this subject based on the ideXlab platform.
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Complement anaphylatoxin receptors C3aR and C5aR are required in the pathogenesis of experimental Autoimmune Uveitis.
Journal of leukocyte biology, 2015Co-Authors: Lingjun Zhang, Rachel R. Caspi, Chi-chao Chan, Brent A. Bell, Neal S. Peachey, John J. Fung, Xiaoming Zhang, Feng LinAbstract:Recent studies have suggested that reagents inhibiting complement activation could be effective in treating T cell mediated Autoimmune diseases such as Autoimmune Uveitis. However, the precise role of the complement anaphylatoxin receptors (C3a and C5a receptors) in the pathogenesis of Autoimmune Uveitis remains elusive and controversial. We induced experimental Autoimmune Uveitis in mice deficient or sufficient in both C3a and C5a receptors and rigorously compared their retinal phenotype using various imaging techniques, including indirect ophthalmoscopy, confocal scanning laser ophthalmoscopy, spectral domain optical coherence tomography, topical endoscopic fundus imaging, and histopathological analysis. We also assessed retinal function using electroretinography. Moreover, we performed Ag-specific T cell recall assays and T cell adoptive transfer experiments to compare pathogenic T cell activity between wild-type and knockout mice with experimental Autoimmune Uveitis. These experiments showed that C3a receptor/C5a receptor-deficient mice developed much less severe Uveitis than did control mice using all retinal examination methods and that these mice had reduced pathogenic T cell responses. Our data demonstrate that both complement anaphylatoxin receptors are important for the development of experimental Autoimmune Uveitis, suggesting that targeting these receptors could be a valid approach for treating patients with Autoimmune Uveitis.
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retina specific t regulatory cells bring about resolution and maintain remission of Autoimmune Uveitis
Journal of Immunology, 2015Co-Authors: Phyllis B. Silver, Chi-chao Chan, Reiko Horai, Yingyos Jittayasothorn, Jun Chen, Rafael Villasmil, Muge R Kesen, Rachel R. CaspiAbstract:Experimental Autoimmune Uveitis (EAU) induced in mice by immunization with the retinal Ag interphotoreceptor retinoid-binding protein (IRBP) is a model of human Autoimmune Uveitis. We examined whether T regulatory cells (Tregs) found in uveitic eyes are IRBP specific, functionally suppressive, and play a role in natural resolution of disease and in maintenance of remission. Progressive increase of Foxp3(+) Treg to T effector cell (Teff) ratio in uveitic eyes correlated with resolution of disease. At peak disease, up to 20% of Tregs (CD4(+)Foxp3(+)) and up to 60% of Teffs (CD4(+)Foxp3(-)) were IRBP specific, whereas in lymphoid organs retina-specific T cells were undetectable. Tregs isolated from eyes of mice with EAU efficiently suppressed IRBP-specific responses of Teffs from the same eyes. Importantly, systemic depletion of Tregs at peak disease delayed resolution of EAU, and their depletion after resolution triggered a relapse. This could be partially duplicated by depletion of Tregs locally within the eye. Thus, the T cell infiltrate in uveitic eyes of normal mice with a polyclonal T cell repertoire is highly enriched in IRBP-specific Tregs and Teffs. Unlike what has been reported for Tregs in other inflammatory sites, Tregs from uveitic eyes appear unimpaired functionally. Finally, Foxp3(+) Tregs play a role in the natural resolution of Uveitis and in the maintenance of remission, which occurs at least in part through an effect that is local to the eye.
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Aquaporin expression in blood-retinal barrier cells during experimental Autoimmune Uveitis.
Molecular vision, 2010Co-Authors: Elie Motulsky, Chi-chao Chan, Philippe Koch, Sarah Janssens, Maité Liénart, Anne-marie Vanbellinghen, Nargis Bolaky, Laure Caspers, Maria-dolores Martin-martinezAbstract:Purpose Blood-retinal barrier (BRB) breakdown and retinal edema are major complications of Autoimmune Uveitis and could be related to deregulation of aquaporin (AQP) expression. We have therefore evaluated the expression of AQP1 and AQP4 on BRB cells during experimental Autoimmune Uveitis (EAU) in mice.
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Mouse Models of Experimental Autoimmune Uveitis
Ophthalmic research, 2008Co-Authors: Rachel R. Caspi, Phyllis B. Silver, Dror Luger, Jun Tang, Lizette M. Cortes, Giuseppina Pennesi, Mary J. Mattapallil, Chi-chao ChanAbstract:The mouse model of experimental Autoimmune Uveitis, induced by immunization of mice with the retinal protein IRBP, was developed in our laboratory 20 years ago and published in 1988. Since that time it has been adopted by many investigators and has given rise to many studies that helped elucidate genetic influences, dissect the basic mechanisms of pathogenesis and test novel immunotherapeutic paradigms. The current overview will summarize the salient features of the experimental Autoimmune Uveitis model and discuss its mechanisms.
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Pregnancy Ameliorates Induction and Expression of Experimental Autoimmune Uveitis
Journal of immunology (Baltimore Md. : 1950), 1999Co-Authors: Rajeev K. Agarwal, B. Wiggert, Chi-chao Chan, Rachel R. CaspiAbstract:Female patients suffering from Autoimmune Uveitis are reported to experience a temporary remission during pregnancy. Experimental Autoimmune Uveitis (EAU) is a model for human Uveitis. Here we examine the effect of pregnancy on the development of EAU and its associated immunological responses. Susceptible C57BL/6 mice were immunized with interphotoreceptor retinoid-binding protein (IRBP). EAU scores and Ag-specific responses were evaluated 21 days later. Mice immunized during pregnancy developed significantly less EAU than nonpregnant controls. Their lymph node cells and splenocytes produced a distinct pattern of cytokines in response to IRBP: reduced IFN-γ and IL-12 p40, but unchanged levels of TNF-α, IL-4, IL-5, and IL-10. Anti-IRBP Ab isotypes revealed an up-regulation of IgG1, indicating a possible Th2 bias at the humoral level. Ag-specific proliferation and delayed hypersensitivity, as well as mitogen-induced IFN-γ production, remained undiminished, arguing against an overall immune deficit. Interestingly, pregnant mice that received an infusion of IRBP-primed lymphoid cells from nonpregnant donors also developed reduced EAU, suggesting that pregnancy suppresses not only the generation, but also the function of mature uveitogenic effector T cells. Pregnant mice at the time of immunization exhibited elevated levels of TGF-β, but not of IL-10, in the serum. We suggest that protection from EAU during pregnancy is due primarily to a selective reduction of Ag-specific Th1 responses with only marginal enhancement of Th2 function, and that these effects may in part be secondary to elevated systemic levels of TGF-β.
Hui Shao - One of the best experts on this subject based on the ideXlab platform.
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Adenosine receptor activation in the Th17 Autoimmune responses of experimental Autoimmune Uveitis.
Cellular immunology, 2018Co-Authors: Dongchun Liang, Henry J. Kaplan, Hui Shao, Willi K. Born, Deming SunAbstract:Abstract Th17-type autoreactive T cells contribute to pathogenicity in Autoimmune diseases, including Autoimmune Uveitis. However, the mechanisms of regulation of Th17 cell activities remain unsolved and are likely to be tissue- and disease specific. In this review, we have summarized our studies from the murine model of experimental Autoimmune Uveitis (EAU). The results demonstrate that γδ T cells have a regulatory effect on Th17 response. The regulatory effects of γδ T cells depend on their action state. Activated γδ T cells express significantly high levels of adenosine receptor A2 (A2AR) but low CD73. Both molecules are crucially involved in adenosine generation, thus modifying T cell responses. While the increased expression of A2AR-allows activated γδ T cells to bind adenosine more effectively than other immune cells, the decreased CD73 restricts their ability to convert AMP to adenosine. Adenosine affects Th1 and Th17 Autoimmune responses differently. Its activation of γδ T cells shifts the Th1/Th17 balance towards the Th17 autoreactivity.
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Correction: Regulation of Adenosine Deaminase on Induced Mouse Experimental Autoimmune Uveitis.
Journal of immunology (Baltimore Md. : 1950), 2017Co-Authors: Dongchun Liang, Henry J. Kaplan, Hui Shao, Aijun Zuo, Ronglan Zhao, Deming SunAbstract:Liang, D., A. Zuo, R. Zhao, H. Shao, H. J. Kaplan, and D. Sun. 2016. Regulation of adenosine deaminase on induced mouse experimental Autoimmune Uveitis. J. Immunol . 196: [2646–2654][1]. The authors revised the grant footnote to include additional funding information. The corrected footnote is
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Functional Conversion and Dominance of γδ T Subset in Mouse Experimental Autoimmune Uveitis.
Journal of immunology (Baltimore Md. : 1950), 2017Co-Authors: Dongchun Liang, Henry J. Kaplan, Hui Shao, Hong Nian, Deming SunAbstract:We have previously shown that activated γδ T cells have a much stronger proinflammatory effect in the development of experimental Autoimmune Uveitis than their nonactivated counterparts. Our present study explored γδ T cell subsets are functionally distinct in Autoimmune pathogenesis and determined the pathogenic contribution of biased Vγ4+ γδ T cell activation in this disease. By systematically comparing two major peripheral γδ T cell subsets, the Vγ1+ and the Vγ4+ cells, we found that the Vγ4+ cells were readily activated in B6 mice during experimental Autoimmune Uveitis development, whereas Vγ1+ cells remained nonactivated. Cytokines that were abundantly found in the serum of immunized mice activated Vγ4+, but did not activate Vγ1+, cells. The Vγ4+ cells had a strong proinflammatory activity, whereas the Vγ1+ cells remained nonactivated when tested immediately after isolation from immunized mice. However, when the Vγ1+ cells were activated in vitro, they promoted inflammation. Our results demonstrated that activation is a major factor in switching the enhancing and inhibiting effects of both Vγ1+ and Vγ4+ γδ T cell subsets, and that γδ T cell subsets differ greatly in their activation requirements. Whether the enhancing or inhibiting function of γδ T cells is dominant is mainly determined by the proportion of the γδ T cells that are activated versus the proportion not activated.
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Therapeutic effects of mesenchymal stem cells administered at later phase of recurrent experimental Autoimmune Uveitis.
International journal of ophthalmology, 2016Co-Authors: Ping-ting Zhao, Lingjun Zhang, Hui Shao, Lingling Bai, Lijie Dong, Xun Liu, Xiaomin ZhangAbstract:AIM To test the therapeutic effects of delayed treatment of mesenchymal stem cells (MSCs) in recurrent experimental Autoimmune Uveitis (rEAU).
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Long-term therapeutic effects of mesenchymal stem cells compared to dexamethasone on recurrent experimental Autoimmune Uveitis of rats.
Investigative ophthalmology & visual science, 2014Co-Authors: Lingjun Zhang, Hui Shao, Lingling Bai, Xun Liu, Hong Nian, Hui Zheng, Yan Zhang, Lijie DongAbstract:Purpose. We tested the long-term effects of different regimens of mesenchymal stem cell (MSC) administration in a recurrent experimental Autoimmune Uveitis (rEAU) model in rats, and compared the efficacy of MSC to that of dexamethasone (DEX).
Tomáš Kučera - One of the best experts on this subject based on the ideXlab platform.
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Metronidazole Attenuates the Intensity of Inflammation in Experimental Autoimmune Uveitis.
Folia biologica, 2019Co-Authors: P Seidler Stangova, A Klimova, Tomáš Kučera, Jarmila Heissigerova, O Dusek, Petra SvozilkovaAbstract:Autoimmune Uveitis is a serious sightthreatening disease that in many cases fails to respond to conventional immunosuppressive or biological therapy. Experimental models used in research allow more detailed study of pathogenesis of the Autoimmune process and testing new therapeutic strategies. Recent results show that infection can trigger Autoimmune diseases, and some commensal microorganisms are essential in causing disease activity. The aim of this work was to assess the effect of broadspectrum antibiotics - combination of metronidazole and ciprofloxacin or metronidazole alone - on the intensity of intraocular inflammation in experimental Autoimmune Uveitis (EAU). EAU was induced in mouse strain C57BL/6J by interphotoreceptor retinoid- binding protein in complete Freund's adjuvant and pertussis toxin. The grade of Uveitis was assessed clinically and histologically in haematoxylin and eosin- stained tissues. Lymphocytes and macrophages were detected in cryosections using the immunoperoxidase method with antibodies. The therapy was commenced one week before EAU induction and continued throughout the experiment. In addition, metronidazole treatment was also started two weeks before EAU induction. Antibiotics significantly reduced the intensity of Uveitis compared to the control group (P < 0.05). The effects of combination of ciprofloxacin and metronidazole and of metronidazole alone were similar when the therapy started one week before EAU induction (P < 0.05). Metronidazole commenced two weeks before EAU induction and throughout the experiment suppressed the intensity of EAU with even higher statistical significance (P < 0.0001). It can be assumed that the high protective effect of metronidazole on EAU intensity may be due not only to its antimicrobial effect, but also to its immunomodulatory activity.
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The Clinical Signs of Experimental Autoimmune Uveitis
Ceska a slovenska oftalmologie : casopis Ceske oftalmologicke spolecnosti a Slovenske oftalmologicke spolecnosti, 2016Co-Authors: A Klimova, Seidler Štangová P, Petra Svozilkova, Tomáš Kučera, Jarmila HeissigerovaAbstract:INTRODUCTION Autoimmune Uveitis is a sight threatening disease which in many cases fails to respond to conventional immunosuppressive or biological therapy. The research in experimental models of Autoimmune Uveitis helps to find new therapeutical strategies. The aim of this study is to present the clinical and histological signs of experimental Autoimmune Uveitis (EAU) in mice. METHODS EAU was induced in C57BL/6 mice by subcutaneous application of IRBP (interphotoreceptor retinoid binding protein) in complete Freunds adjuvant and intraperitoneal application of pertussis toxin. Clinical evaluation of Uveitis was performed in vivo using special imaging system with otoscope. Histological evaluation of Uveitis was performed at day 35 post induction of EAU on hematoxylin and eosin stained frozen sections. Clinical and histological grading was used to assess the inflammation intensity of EAU. RESULTS The intensity of inflammation is depicted on representative fundus images and histological images of retina at day 35 post induction. CONCLUSION The model of EAU is robust and reproducible and allows us to study the immunopathological mechanisms of inflammation and its regulation. The inflammatory signs in our model are similar to findings of posterior Uveitis of Autoimmune etiology in humans, thus we may apply our experimental results in human medicine.
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Mycophenolate mofetil and cyclophosphamide treatment suppress inflammation intensity in experimental model of Autoimmune Uveitis
Acta Ophthalmologica, 2014Co-Authors: A Klimova, Petra Svozilkova, Jarmila Heissigerova, P Seidler Stangova, Tomáš KučeraAbstract:Purpose The research in experimental models of Autoimmune Uveitis helps to find new therapeutical strategies. The aim of this study is to compare the effect of cyclophosphamide (CPA), mycophenolate mofetil (MMF) and golimumab on inflammation intensity in mice model of experimental Autoimmune Uveitis (EAU). Methods EAU was induced in C57BL/6 mice by subcutaneous application of IRBP (interphotoreceptor retinoid binding protein) in complete Freund’s adjuvant and pertussis toxin. CPA was injected intraperitoneally in a single dose of 100 mg/kg, MMF intraperitoneally daily in a dose of 30 and 50 mg/kg, golimumab subcutaneously weekly in a dose of 70 mg/kg. Mice with EAU without treatment and group with EAU with sham treatment served as controls. Histological grading of Uveitis at day 35 post induction of EAU was used. Results The comparison of intensity of inflammation in group of treated and untreated mice shows that MMF significantly suppressed the inflammation (p˂0,05). The absolute suppression of inflammation by CPA (p˂0,0001) was shown. On the contrary, golimumab enhanced the ocular inflammation. Conclusion In this study, we have confirmed the efficacy of CPA and MMF in treatment of posterior Uveitis, which supports its use in human medicine. This project was supported by grant IGA MZ NT/14017-3/2013 and SVV-266505/2013.
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Mycophenolate mofetil and cyclophosphamide treatments suppress inflammation intensity in an experimental model of Autoimmune Uveitis.
Folia biologica, 2014Co-Authors: A Klimova, Petra Svozilkova, Jarmila Heissigerova, Seidler Štanogová P, Tomáš KučeraAbstract:In human, Autoimmune Uveitis is a leading cause of visual disability and ranks with diabetic retinopathy as a major source of blind registrations in developed countries. Since most cases of non-infectious Uveitis are considered to be Autoimmune or at least immune-mediated, the management of such patients has rested on appropriate immunosuppression. Some patients, however, despite maximal immunotherapy, fail to respond or are seriously intolerant of the drug therapies. Since its establishment 20 years ago, the model of experimental Autoimmune uveoretinitis has served as a useful template for novel therapeutic approaches. The aim of our study was to compare the efficacy of mycophenolate mofetil and cyclophosphamide and golimumab treatment in the mouse model of experimental Autoimmune Uveitis. The intensity of intraocular inflammation was evaluated histologically in the treatment and control groups. Experimental Autoimmune Uveitis has been induced in mouse strain C57BL/6 by subcutaneous application of interphotoreceptor retinoid binding protein in complete Freund's adjuvant and pertussis toxin. The treatment was commenced on the day of Uveitis induction. Cyclophosphamide was applied intraperitoneally in a single dose (100 mg/kg), mycophenolate mofetil intraperitoneally daily (30 mg/kg or 50 mg/kg), golimumab subcutaneously weekly (70 mg/kg). Sham intraperitoneal injection of a placebo (aqua pro injectione) and untreated mice with experimental Autoimmune Uveitis served as controls. The results show statistically significant suppression of experimental Uveitis both with mycophenolate mofetil and with cyclophosphamide, and thus support its use in human medicine.
