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Rachel R. Caspi – One of the best experts on this subject based on the ideXlab platform.

  • AS101 ameliorates experimental Autoimmune Uveitis by regulating Th1 and Th17 responses and inducing Treg cells
    Journal of autoimmunity, 2019
    Co-Authors: So Jin Bing, Phyllis B. Silver, Reiko Horai, Itay Israel Shemesh, Wai Po Chong, Yingyos Jittayasothorn, Benjamin Sredni, Rachel R. Caspi

    Abstract:

    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, 2018
    Co-Authors: Lingjun Zhang, Rachel R. Caspi, Brent A. Bell, Wen Qiu, Nina Dvorina, William M. Baldwin, Nora G. Singer, Timothy S. Kern, David A. Fox

    Abstract:

    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, 2015
    Co-Authors: Jennifer L. Kielczewski, Rachel R. Caspi

    Abstract:

    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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Lingjun Zhang – One of the best experts on this subject based on the ideXlab platform.

  • Targeting CD6 for the treatment of experimental Autoimmune Uveitis.
    Journal of autoimmunity, 2018
    Co-Authors: Lingjun Zhang, Rachel R. Caspi, Brent A. Bell, Wen Qiu, Nina Dvorina, William M. Baldwin, Nora G. Singer, Timothy S. Kern, David A. Fox

    Abstract:

    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, 2016
    Co-Authors: Ping-ting Zhao, Lingjun Zhang, Hui Shao, Lingling Bai, Lijie Dong, Xun Liu, Xiaomin Zhang

    Abstract:

    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, 2015
    Co-Authors: Lingjun Zhang, Rachel R. Caspi, Chi-chao Chan, Brent A. Bell, Neal S. Peachey, John J. Fung, Xiaoming Zhang, Feng Lin

    Abstract:

    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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Chi-chao Chan – One of the best experts on this subject based on the ideXlab platform.

  • Complement anaphylatoxin receptors C3aR and C5aR are required in the pathogenesis of experimental Autoimmune Uveitis.
    Journal of leukocyte biology, 2015
    Co-Authors: Lingjun Zhang, Rachel R. Caspi, Chi-chao Chan, Brent A. Bell, Neal S. Peachey, John J. Fung, Xiaoming Zhang, Feng Lin

    Abstract:

    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, 2015
    Co-Authors: Phyllis B. Silver, Chi-chao Chan, Reiko Horai, Yingyos Jittayasothorn, Jun Chen, Rafael Villasmil, Muge R Kesen, Rachel R. Caspi

    Abstract:

    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, 2010
    Co-Authors: Elie Motulsky, Chi-chao Chan, Philippe Koch, Sarah Janssens, Maité Liénart, Anne-marie Vanbellinghen, Nargis Bolaky, Laure Caspers, Maria-dolores Martin-martinez

    Abstract:

    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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