Intraocular DHODH-inhibitor PP-001 suppresses relapsing experimental uveitis and cytokine production of human lymphocytes, but not of RPE cells
Abstract Background Uveitis is a potentially blinding inflammatory disease of the inner eye with a high unmet need for new therapeutic interventions. Here, we wanted to investigate the suppressive effect of the intraocular application of the small molecule dihydroorotate dehydrogenase (DHODH)-inhibi...
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BMC
2018-02-01
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Series: | Journal of Neuroinflammation |
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Online Access: | http://link.springer.com/article/10.1186/s12974-018-1088-6 |
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author | Maria Diedrichs-Möhring Sandy Niesik Claudia S. Priglinger Stephan R. Thurau Franz Obermayr Stefan Sperl Gerhild Wildner |
author_facet | Maria Diedrichs-Möhring Sandy Niesik Claudia S. Priglinger Stephan R. Thurau Franz Obermayr Stefan Sperl Gerhild Wildner |
author_sort | Maria Diedrichs-Möhring |
collection | DOAJ |
description | Abstract Background Uveitis is a potentially blinding inflammatory disease of the inner eye with a high unmet need for new therapeutic interventions. Here, we wanted to investigate the suppressive effect of the intraocular application of the small molecule dihydroorotate dehydrogenase (DHODH)-inhibitor PP-001 on experimental relapsing rat uveitis and furthermore determine its effect on proliferation and cytokine secretion of human peripheral blood lymphocytes (PBL) and human retinal pigment epithelial (RPE) cells in vitro. Methods Spontaneously relapsing uveitis was induced in rats by immunization with interphotoreceptor retinoid-binding protein (IRBP) peptide R14. PP-001 was injected intravitreally after resolution of the primary disease to investigate further relapses. Proliferation and metabolic activity of phytohemagglutinin (PHA)-stimulated human peripheral lymphocytes with and without PP-001 and cytokine secretion were determined by XTT assay and bioplex bead assay. The RPE cell line ARPE-19 as well as primary human RPE cells treated with PP-001 or anti-vascular endothelial growth factor (VEGF) antibody bevacizumab were also investigated for metabolic activity and cytokine/chemokine secretion. Results Injection of PP-001 into rat eyes reduced the number of relapses by 70%, from 20 relapses (57% of the rats affected) in the control group to 6 relapses (33% of the rats) in the treatment group. In human PBL cultures, PP-001 reduced the proliferation in a dose-dependent manner. The secretion of several cytokines such as IL-17, IFN-γ, and VEGF was suppressed by PP-001, as previously observed with rat T cells in the experimental autoimmune uveitis (EAU) model. In contrast, human RPE cells were not affected by PP-001, while the anti-VEGF antibody bevacizumab severely impaired the secretion of various cytokines including VEGF. Conclusions For the first time, intravitreal injection of PP-001 demonstrated an effective, but transient reduction of relapses in the rat EAU model. In vitro PP-001 suppressed proliferation and cytokine/chemokine secretion of human lymphocytes, while neither human RPE cell line ARPE-19 nor primary RPE cells were affected. |
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issn | 1742-2094 |
language | English |
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spelling | doaj.art-35027cc6f0494c0a811224b2e45aa2f22022-12-22T02:20:57ZengBMCJournal of Neuroinflammation1742-20942018-02-0115111110.1186/s12974-018-1088-6Intraocular DHODH-inhibitor PP-001 suppresses relapsing experimental uveitis and cytokine production of human lymphocytes, but not of RPE cellsMaria Diedrichs-Möhring0Sandy Niesik1Claudia S. Priglinger2Stephan R. Thurau3Franz Obermayr4Stefan Sperl5Gerhild Wildner6Section of Immunobiology, Department of Ophthalmology, University Hospital, LMU MunichSection of Immunobiology, Department of Ophthalmology, University Hospital, LMU MunichDepartment of Ophthalmology, University Hospital, LMU MunichSection of Immunobiology, Department of Ophthalmology, University Hospital, LMU MunichPanoptes Pharma GmbHPanoptes Pharma GmbHSection of Immunobiology, Department of Ophthalmology, University Hospital, LMU MunichAbstract Background Uveitis is a potentially blinding inflammatory disease of the inner eye with a high unmet need for new therapeutic interventions. Here, we wanted to investigate the suppressive effect of the intraocular application of the small molecule dihydroorotate dehydrogenase (DHODH)-inhibitor PP-001 on experimental relapsing rat uveitis and furthermore determine its effect on proliferation and cytokine secretion of human peripheral blood lymphocytes (PBL) and human retinal pigment epithelial (RPE) cells in vitro. Methods Spontaneously relapsing uveitis was induced in rats by immunization with interphotoreceptor retinoid-binding protein (IRBP) peptide R14. PP-001 was injected intravitreally after resolution of the primary disease to investigate further relapses. Proliferation and metabolic activity of phytohemagglutinin (PHA)-stimulated human peripheral lymphocytes with and without PP-001 and cytokine secretion were determined by XTT assay and bioplex bead assay. The RPE cell line ARPE-19 as well as primary human RPE cells treated with PP-001 or anti-vascular endothelial growth factor (VEGF) antibody bevacizumab were also investigated for metabolic activity and cytokine/chemokine secretion. Results Injection of PP-001 into rat eyes reduced the number of relapses by 70%, from 20 relapses (57% of the rats affected) in the control group to 6 relapses (33% of the rats) in the treatment group. In human PBL cultures, PP-001 reduced the proliferation in a dose-dependent manner. The secretion of several cytokines such as IL-17, IFN-γ, and VEGF was suppressed by PP-001, as previously observed with rat T cells in the experimental autoimmune uveitis (EAU) model. In contrast, human RPE cells were not affected by PP-001, while the anti-VEGF antibody bevacizumab severely impaired the secretion of various cytokines including VEGF. Conclusions For the first time, intravitreal injection of PP-001 demonstrated an effective, but transient reduction of relapses in the rat EAU model. In vitro PP-001 suppressed proliferation and cytokine/chemokine secretion of human lymphocytes, while neither human RPE cell line ARPE-19 nor primary RPE cells were affected.http://link.springer.com/article/10.1186/s12974-018-1088-6Experimental autoimmune uveitisRat modelDHODH-inhibitorLymphocytesRPE cellsCytokines |
spellingShingle | Maria Diedrichs-Möhring Sandy Niesik Claudia S. Priglinger Stephan R. Thurau Franz Obermayr Stefan Sperl Gerhild Wildner Intraocular DHODH-inhibitor PP-001 suppresses relapsing experimental uveitis and cytokine production of human lymphocytes, but not of RPE cells Journal of Neuroinflammation Experimental autoimmune uveitis Rat model DHODH-inhibitor Lymphocytes RPE cells Cytokines |
title | Intraocular DHODH-inhibitor PP-001 suppresses relapsing experimental uveitis and cytokine production of human lymphocytes, but not of RPE cells |
title_full | Intraocular DHODH-inhibitor PP-001 suppresses relapsing experimental uveitis and cytokine production of human lymphocytes, but not of RPE cells |
title_fullStr | Intraocular DHODH-inhibitor PP-001 suppresses relapsing experimental uveitis and cytokine production of human lymphocytes, but not of RPE cells |
title_full_unstemmed | Intraocular DHODH-inhibitor PP-001 suppresses relapsing experimental uveitis and cytokine production of human lymphocytes, but not of RPE cells |
title_short | Intraocular DHODH-inhibitor PP-001 suppresses relapsing experimental uveitis and cytokine production of human lymphocytes, but not of RPE cells |
title_sort | intraocular dhodh inhibitor pp 001 suppresses relapsing experimental uveitis and cytokine production of human lymphocytes but not of rpe cells |
topic | Experimental autoimmune uveitis Rat model DHODH-inhibitor Lymphocytes RPE cells Cytokines |
url | http://link.springer.com/article/10.1186/s12974-018-1088-6 |
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