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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Main Authors: Maria Diedrichs-Möhring, Sandy Niesik, Claudia S. Priglinger, Stephan R. Thurau, Franz Obermayr, Stefan Sperl, Gerhild Wildner
Format: Article
Language:English
Published: BMC 2018-02-01
Series:Journal of Neuroinflammation
Subjects:
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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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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