Interleukin 35-Producing Exosomes Suppress Neuroinflammation and Autoimmune Uveitis

Corticosteroids are effective therapy for autoimmune diseases but serious adverse effects preclude their prolonged use. However, immune-suppressive biologics that inhibit lymphoid proliferation are now in use as corticosteroid sparing-agents but with variable success; thus, the need to develop alternative immune-suppressive approaches including cell-based therapies. Efficacy of ex-vivo-generated IL-35-producing regulatory B-cells (i35-Bregs) in suppressing/ameliorating encephalomyelitis or uveitis in mouse models of multiple sclerosis or uveitis, respectively, is therefore a promising therapeutic approach for CNS autoimmune diseases. However, i35-Breg therapy in human uveitis would require producing autologous Bregs from each patient to avoid immune-rejection. Because exosomes exhibit minimal toxicity and immunogenicity, we investigated whether i35-Bregs release exosomes that can be exploited therapeutically. Here, we demonstrate that i35-Bregs release exosomes that contain IL-35 (i35-Exosomes). In this proof-of-concept study, we induced experimental autoimmune uveitis (EAU), monitored EAU progression by fundoscopy, histology, optical coherence tomography and electroretinography, and investigated whether i35-Exosomes treatment would suppress uveitis. Mice treated with i35-Exosomes developed mild EAU with low EAU scores and disease protection correlated with expansion of IL-10 and IL-35 secreting Treg cells with concomitant suppression of Th17 responses. In contrast, significant increase of Th17 cells in vitreous and retina of control mouse eyes was accompanied by severe choroiditis, massive retinal-folds, and photoreceptor cell damage. These hallmark features of severe uveitis were absent in exosome-treated mice and visual impairment detected by ERG was modest compared to control mice. Absence of toxicity or alloreactivity associated with exosomes thus makes i35-Exosomes attractive therapeutic option for delivering IL-35 into CNS tissues. Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Minkyung Kang [verfasserIn] Jin Kyeong Choi [verfasserIn] Yingyos Jittayasothorn [verfasserIn] Charles E. Egwuagu [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2020

Schlagwörter:	exosome regulatory B-cell bregs uveitis experimental autoimmune uveitis (EAU)

Übergeordnetes Werk:	In: Frontiers in Immunology - Frontiers Media S.A., 2011, 11(2020)
Übergeordnetes Werk:	volume:11 ; year:2020

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3389/fimmu.2020.01051

Katalog-ID:	DOAJ003714845

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allfields	10.3389/fimmu.2020.01051 doi (DE-627)DOAJ003714845 (DE-599)DOAJeb396c992c964078a55da83fd46554d6 DE-627 ger DE-627 rakwb eng RC581-607 Minkyung Kang verfasserin aut Interleukin 35-Producing Exosomes Suppress Neuroinflammation and Autoimmune Uveitis 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Corticosteroids are effective therapy for autoimmune diseases but serious adverse effects preclude their prolonged use. However, immune-suppressive biologics that inhibit lymphoid proliferation are now in use as corticosteroid sparing-agents but with variable success; thus, the need to develop alternative immune-suppressive approaches including cell-based therapies. Efficacy of ex-vivo-generated IL-35-producing regulatory B-cells (i35-Bregs) in suppressing/ameliorating encephalomyelitis or uveitis in mouse models of multiple sclerosis or uveitis, respectively, is therefore a promising therapeutic approach for CNS autoimmune diseases. However, i35-Breg therapy in human uveitis would require producing autologous Bregs from each patient to avoid immune-rejection. Because exosomes exhibit minimal toxicity and immunogenicity, we investigated whether i35-Bregs release exosomes that can be exploited therapeutically. Here, we demonstrate that i35-Bregs release exosomes that contain IL-35 (i35-Exosomes). In this proof-of-concept study, we induced experimental autoimmune uveitis (EAU), monitored EAU progression by fundoscopy, histology, optical coherence tomography and electroretinography, and investigated whether i35-Exosomes treatment would suppress uveitis. Mice treated with i35-Exosomes developed mild EAU with low EAU scores and disease protection correlated with expansion of IL-10 and IL-35 secreting Treg cells with concomitant suppression of Th17 responses. In contrast, significant increase of Th17 cells in vitreous and retina of control mouse eyes was accompanied by severe choroiditis, massive retinal-folds, and photoreceptor cell damage. These hallmark features of severe uveitis were absent in exosome-treated mice and visual impairment detected by ERG was modest compared to control mice. Absence of toxicity or alloreactivity associated with exosomes thus makes i35-Exosomes attractive therapeutic option for delivering IL-35 into CNS tissues. exosome regulatory B-cell bregs uveitis experimental autoimmune uveitis (EAU) Immunologic diseases. Allergy Jin Kyeong Choi verfasserin aut Jin Kyeong Choi verfasserin aut Yingyos Jittayasothorn verfasserin aut Charles E. Egwuagu verfasserin aut In Frontiers in Immunology Frontiers Media S.A., 2011 11(2020) (DE-627)657998354 (DE-600)2606827-8 16643224 nnns volume:11 year:2020 https://doi.org/10.3389/fimmu.2020.01051 kostenfrei https://doaj.org/article/eb396c992c964078a55da83fd46554d6 kostenfrei https://www.frontiersin.org/article/10.3389/fimmu.2020.01051/full kostenfrei https://doaj.org/toc/1664-3224 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2020
spelling	10.3389/fimmu.2020.01051 doi (DE-627)DOAJ003714845 (DE-599)DOAJeb396c992c964078a55da83fd46554d6 DE-627 ger DE-627 rakwb eng RC581-607 Minkyung Kang verfasserin aut Interleukin 35-Producing Exosomes Suppress Neuroinflammation and Autoimmune Uveitis 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Corticosteroids are effective therapy for autoimmune diseases but serious adverse effects preclude their prolonged use. However, immune-suppressive biologics that inhibit lymphoid proliferation are now in use as corticosteroid sparing-agents but with variable success; thus, the need to develop alternative immune-suppressive approaches including cell-based therapies. Efficacy of ex-vivo-generated IL-35-producing regulatory B-cells (i35-Bregs) in suppressing/ameliorating encephalomyelitis or uveitis in mouse models of multiple sclerosis or uveitis, respectively, is therefore a promising therapeutic approach for CNS autoimmune diseases. However, i35-Breg therapy in human uveitis would require producing autologous Bregs from each patient to avoid immune-rejection. Because exosomes exhibit minimal toxicity and immunogenicity, we investigated whether i35-Bregs release exosomes that can be exploited therapeutically. Here, we demonstrate that i35-Bregs release exosomes that contain IL-35 (i35-Exosomes). In this proof-of-concept study, we induced experimental autoimmune uveitis (EAU), monitored EAU progression by fundoscopy, histology, optical coherence tomography and electroretinography, and investigated whether i35-Exosomes treatment would suppress uveitis. Mice treated with i35-Exosomes developed mild EAU with low EAU scores and disease protection correlated with expansion of IL-10 and IL-35 secreting Treg cells with concomitant suppression of Th17 responses. In contrast, significant increase of Th17 cells in vitreous and retina of control mouse eyes was accompanied by severe choroiditis, massive retinal-folds, and photoreceptor cell damage. These hallmark features of severe uveitis were absent in exosome-treated mice and visual impairment detected by ERG was modest compared to control mice. Absence of toxicity or alloreactivity associated with exosomes thus makes i35-Exosomes attractive therapeutic option for delivering IL-35 into CNS tissues. exosome regulatory B-cell bregs uveitis experimental autoimmune uveitis (EAU) Immunologic diseases. Allergy Jin Kyeong Choi verfasserin aut Jin Kyeong Choi verfasserin aut Yingyos Jittayasothorn verfasserin aut Charles E. Egwuagu verfasserin aut In Frontiers in Immunology Frontiers Media S.A., 2011 11(2020) (DE-627)657998354 (DE-600)2606827-8 16643224 nnns volume:11 year:2020 https://doi.org/10.3389/fimmu.2020.01051 kostenfrei https://doaj.org/article/eb396c992c964078a55da83fd46554d6 kostenfrei https://www.frontiersin.org/article/10.3389/fimmu.2020.01051/full kostenfrei https://doaj.org/toc/1664-3224 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2020
allfields_unstemmed	10.3389/fimmu.2020.01051 doi (DE-627)DOAJ003714845 (DE-599)DOAJeb396c992c964078a55da83fd46554d6 DE-627 ger DE-627 rakwb eng RC581-607 Minkyung Kang verfasserin aut Interleukin 35-Producing Exosomes Suppress Neuroinflammation and Autoimmune Uveitis 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Corticosteroids are effective therapy for autoimmune diseases but serious adverse effects preclude their prolonged use. However, immune-suppressive biologics that inhibit lymphoid proliferation are now in use as corticosteroid sparing-agents but with variable success; thus, the need to develop alternative immune-suppressive approaches including cell-based therapies. Efficacy of ex-vivo-generated IL-35-producing regulatory B-cells (i35-Bregs) in suppressing/ameliorating encephalomyelitis or uveitis in mouse models of multiple sclerosis or uveitis, respectively, is therefore a promising therapeutic approach for CNS autoimmune diseases. However, i35-Breg therapy in human uveitis would require producing autologous Bregs from each patient to avoid immune-rejection. Because exosomes exhibit minimal toxicity and immunogenicity, we investigated whether i35-Bregs release exosomes that can be exploited therapeutically. Here, we demonstrate that i35-Bregs release exosomes that contain IL-35 (i35-Exosomes). In this proof-of-concept study, we induced experimental autoimmune uveitis (EAU), monitored EAU progression by fundoscopy, histology, optical coherence tomography and electroretinography, and investigated whether i35-Exosomes treatment would suppress uveitis. Mice treated with i35-Exosomes developed mild EAU with low EAU scores and disease protection correlated with expansion of IL-10 and IL-35 secreting Treg cells with concomitant suppression of Th17 responses. In contrast, significant increase of Th17 cells in vitreous and retina of control mouse eyes was accompanied by severe choroiditis, massive retinal-folds, and photoreceptor cell damage. These hallmark features of severe uveitis were absent in exosome-treated mice and visual impairment detected by ERG was modest compared to control mice. Absence of toxicity or alloreactivity associated with exosomes thus makes i35-Exosomes attractive therapeutic option for delivering IL-35 into CNS tissues. exosome regulatory B-cell bregs uveitis experimental autoimmune uveitis (EAU) Immunologic diseases. Allergy Jin Kyeong Choi verfasserin aut Jin Kyeong Choi verfasserin aut Yingyos Jittayasothorn verfasserin aut Charles E. Egwuagu verfasserin aut In Frontiers in Immunology Frontiers Media S.A., 2011 11(2020) (DE-627)657998354 (DE-600)2606827-8 16643224 nnns volume:11 year:2020 https://doi.org/10.3389/fimmu.2020.01051 kostenfrei https://doaj.org/article/eb396c992c964078a55da83fd46554d6 kostenfrei https://www.frontiersin.org/article/10.3389/fimmu.2020.01051/full kostenfrei https://doaj.org/toc/1664-3224 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2020
allfieldsGer	10.3389/fimmu.2020.01051 doi (DE-627)DOAJ003714845 (DE-599)DOAJeb396c992c964078a55da83fd46554d6 DE-627 ger DE-627 rakwb eng RC581-607 Minkyung Kang verfasserin aut Interleukin 35-Producing Exosomes Suppress Neuroinflammation and Autoimmune Uveitis 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Corticosteroids are effective therapy for autoimmune diseases but serious adverse effects preclude their prolonged use. However, immune-suppressive biologics that inhibit lymphoid proliferation are now in use as corticosteroid sparing-agents but with variable success; thus, the need to develop alternative immune-suppressive approaches including cell-based therapies. Efficacy of ex-vivo-generated IL-35-producing regulatory B-cells (i35-Bregs) in suppressing/ameliorating encephalomyelitis or uveitis in mouse models of multiple sclerosis or uveitis, respectively, is therefore a promising therapeutic approach for CNS autoimmune diseases. However, i35-Breg therapy in human uveitis would require producing autologous Bregs from each patient to avoid immune-rejection. Because exosomes exhibit minimal toxicity and immunogenicity, we investigated whether i35-Bregs release exosomes that can be exploited therapeutically. Here, we demonstrate that i35-Bregs release exosomes that contain IL-35 (i35-Exosomes). In this proof-of-concept study, we induced experimental autoimmune uveitis (EAU), monitored EAU progression by fundoscopy, histology, optical coherence tomography and electroretinography, and investigated whether i35-Exosomes treatment would suppress uveitis. Mice treated with i35-Exosomes developed mild EAU with low EAU scores and disease protection correlated with expansion of IL-10 and IL-35 secreting Treg cells with concomitant suppression of Th17 responses. In contrast, significant increase of Th17 cells in vitreous and retina of control mouse eyes was accompanied by severe choroiditis, massive retinal-folds, and photoreceptor cell damage. These hallmark features of severe uveitis were absent in exosome-treated mice and visual impairment detected by ERG was modest compared to control mice. Absence of toxicity or alloreactivity associated with exosomes thus makes i35-Exosomes attractive therapeutic option for delivering IL-35 into CNS tissues. exosome regulatory B-cell bregs uveitis experimental autoimmune uveitis (EAU) Immunologic diseases. Allergy Jin Kyeong Choi verfasserin aut Jin Kyeong Choi verfasserin aut Yingyos Jittayasothorn verfasserin aut Charles E. Egwuagu verfasserin aut In Frontiers in Immunology Frontiers Media S.A., 2011 11(2020) (DE-627)657998354 (DE-600)2606827-8 16643224 nnns volume:11 year:2020 https://doi.org/10.3389/fimmu.2020.01051 kostenfrei https://doaj.org/article/eb396c992c964078a55da83fd46554d6 kostenfrei https://www.frontiersin.org/article/10.3389/fimmu.2020.01051/full kostenfrei https://doaj.org/toc/1664-3224 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2020
allfieldsSound	10.3389/fimmu.2020.01051 doi (DE-627)DOAJ003714845 (DE-599)DOAJeb396c992c964078a55da83fd46554d6 DE-627 ger DE-627 rakwb eng RC581-607 Minkyung Kang verfasserin aut Interleukin 35-Producing Exosomes Suppress Neuroinflammation and Autoimmune Uveitis 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Corticosteroids are effective therapy for autoimmune diseases but serious adverse effects preclude their prolonged use. However, immune-suppressive biologics that inhibit lymphoid proliferation are now in use as corticosteroid sparing-agents but with variable success; thus, the need to develop alternative immune-suppressive approaches including cell-based therapies. Efficacy of ex-vivo-generated IL-35-producing regulatory B-cells (i35-Bregs) in suppressing/ameliorating encephalomyelitis or uveitis in mouse models of multiple sclerosis or uveitis, respectively, is therefore a promising therapeutic approach for CNS autoimmune diseases. However, i35-Breg therapy in human uveitis would require producing autologous Bregs from each patient to avoid immune-rejection. Because exosomes exhibit minimal toxicity and immunogenicity, we investigated whether i35-Bregs release exosomes that can be exploited therapeutically. Here, we demonstrate that i35-Bregs release exosomes that contain IL-35 (i35-Exosomes). In this proof-of-concept study, we induced experimental autoimmune uveitis (EAU), monitored EAU progression by fundoscopy, histology, optical coherence tomography and electroretinography, and investigated whether i35-Exosomes treatment would suppress uveitis. Mice treated with i35-Exosomes developed mild EAU with low EAU scores and disease protection correlated with expansion of IL-10 and IL-35 secreting Treg cells with concomitant suppression of Th17 responses. In contrast, significant increase of Th17 cells in vitreous and retina of control mouse eyes was accompanied by severe choroiditis, massive retinal-folds, and photoreceptor cell damage. These hallmark features of severe uveitis were absent in exosome-treated mice and visual impairment detected by ERG was modest compared to control mice. Absence of toxicity or alloreactivity associated with exosomes thus makes i35-Exosomes attractive therapeutic option for delivering IL-35 into CNS tissues. exosome regulatory B-cell bregs uveitis experimental autoimmune uveitis (EAU) Immunologic diseases. Allergy Jin Kyeong Choi verfasserin aut Jin Kyeong Choi verfasserin aut Yingyos Jittayasothorn verfasserin aut Charles E. Egwuagu verfasserin aut In Frontiers in Immunology Frontiers Media S.A., 2011 11(2020) (DE-627)657998354 (DE-600)2606827-8 16643224 nnns volume:11 year:2020 https://doi.org/10.3389/fimmu.2020.01051 kostenfrei https://doaj.org/article/eb396c992c964078a55da83fd46554d6 kostenfrei https://www.frontiersin.org/article/10.3389/fimmu.2020.01051/full kostenfrei https://doaj.org/toc/1664-3224 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2020
language	English
source	In Frontiers in Immunology 11(2020) volume:11 year:2020
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spellingShingle	Minkyung Kang misc RC581-607 misc exosome misc regulatory B-cell misc bregs misc uveitis misc experimental autoimmune uveitis (EAU) misc Immunologic diseases. Allergy Interleukin 35-Producing Exosomes Suppress Neuroinflammation and Autoimmune Uveitis
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topic_title	RC581-607 Interleukin 35-Producing Exosomes Suppress Neuroinflammation and Autoimmune Uveitis exosome regulatory B-cell bregs uveitis experimental autoimmune uveitis (EAU)
topic	misc RC581-607 misc exosome misc regulatory B-cell misc bregs misc uveitis misc experimental autoimmune uveitis (EAU) misc Immunologic diseases. Allergy
topic_unstemmed	misc RC581-607 misc exosome misc regulatory B-cell misc bregs misc uveitis misc experimental autoimmune uveitis (EAU) misc Immunologic diseases. Allergy
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title	Interleukin 35-Producing Exosomes Suppress Neuroinflammation and Autoimmune Uveitis
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title_sort	interleukin 35-producing exosomes suppress neuroinflammation and autoimmune uveitis
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title_auth	Interleukin 35-Producing Exosomes Suppress Neuroinflammation and Autoimmune Uveitis
abstract	Corticosteroids are effective therapy for autoimmune diseases but serious adverse effects preclude their prolonged use. However, immune-suppressive biologics that inhibit lymphoid proliferation are now in use as corticosteroid sparing-agents but with variable success; thus, the need to develop alternative immune-suppressive approaches including cell-based therapies. Efficacy of ex-vivo-generated IL-35-producing regulatory B-cells (i35-Bregs) in suppressing/ameliorating encephalomyelitis or uveitis in mouse models of multiple sclerosis or uveitis, respectively, is therefore a promising therapeutic approach for CNS autoimmune diseases. However, i35-Breg therapy in human uveitis would require producing autologous Bregs from each patient to avoid immune-rejection. Because exosomes exhibit minimal toxicity and immunogenicity, we investigated whether i35-Bregs release exosomes that can be exploited therapeutically. Here, we demonstrate that i35-Bregs release exosomes that contain IL-35 (i35-Exosomes). In this proof-of-concept study, we induced experimental autoimmune uveitis (EAU), monitored EAU progression by fundoscopy, histology, optical coherence tomography and electroretinography, and investigated whether i35-Exosomes treatment would suppress uveitis. Mice treated with i35-Exosomes developed mild EAU with low EAU scores and disease protection correlated with expansion of IL-10 and IL-35 secreting Treg cells with concomitant suppression of Th17 responses. In contrast, significant increase of Th17 cells in vitreous and retina of control mouse eyes was accompanied by severe choroiditis, massive retinal-folds, and photoreceptor cell damage. These hallmark features of severe uveitis were absent in exosome-treated mice and visual impairment detected by ERG was modest compared to control mice. Absence of toxicity or alloreactivity associated with exosomes thus makes i35-Exosomes attractive therapeutic option for delivering IL-35 into CNS tissues.
abstractGer	Corticosteroids are effective therapy for autoimmune diseases but serious adverse effects preclude their prolonged use. However, immune-suppressive biologics that inhibit lymphoid proliferation are now in use as corticosteroid sparing-agents but with variable success; thus, the need to develop alternative immune-suppressive approaches including cell-based therapies. Efficacy of ex-vivo-generated IL-35-producing regulatory B-cells (i35-Bregs) in suppressing/ameliorating encephalomyelitis or uveitis in mouse models of multiple sclerosis or uveitis, respectively, is therefore a promising therapeutic approach for CNS autoimmune diseases. However, i35-Breg therapy in human uveitis would require producing autologous Bregs from each patient to avoid immune-rejection. Because exosomes exhibit minimal toxicity and immunogenicity, we investigated whether i35-Bregs release exosomes that can be exploited therapeutically. Here, we demonstrate that i35-Bregs release exosomes that contain IL-35 (i35-Exosomes). In this proof-of-concept study, we induced experimental autoimmune uveitis (EAU), monitored EAU progression by fundoscopy, histology, optical coherence tomography and electroretinography, and investigated whether i35-Exosomes treatment would suppress uveitis. Mice treated with i35-Exosomes developed mild EAU with low EAU scores and disease protection correlated with expansion of IL-10 and IL-35 secreting Treg cells with concomitant suppression of Th17 responses. In contrast, significant increase of Th17 cells in vitreous and retina of control mouse eyes was accompanied by severe choroiditis, massive retinal-folds, and photoreceptor cell damage. These hallmark features of severe uveitis were absent in exosome-treated mice and visual impairment detected by ERG was modest compared to control mice. Absence of toxicity or alloreactivity associated with exosomes thus makes i35-Exosomes attractive therapeutic option for delivering IL-35 into CNS tissues.
abstract_unstemmed	Corticosteroids are effective therapy for autoimmune diseases but serious adverse effects preclude their prolonged use. However, immune-suppressive biologics that inhibit lymphoid proliferation are now in use as corticosteroid sparing-agents but with variable success; thus, the need to develop alternative immune-suppressive approaches including cell-based therapies. Efficacy of ex-vivo-generated IL-35-producing regulatory B-cells (i35-Bregs) in suppressing/ameliorating encephalomyelitis or uveitis in mouse models of multiple sclerosis or uveitis, respectively, is therefore a promising therapeutic approach for CNS autoimmune diseases. However, i35-Breg therapy in human uveitis would require producing autologous Bregs from each patient to avoid immune-rejection. Because exosomes exhibit minimal toxicity and immunogenicity, we investigated whether i35-Bregs release exosomes that can be exploited therapeutically. Here, we demonstrate that i35-Bregs release exosomes that contain IL-35 (i35-Exosomes). In this proof-of-concept study, we induced experimental autoimmune uveitis (EAU), monitored EAU progression by fundoscopy, histology, optical coherence tomography and electroretinography, and investigated whether i35-Exosomes treatment would suppress uveitis. Mice treated with i35-Exosomes developed mild EAU with low EAU scores and disease protection correlated with expansion of IL-10 and IL-35 secreting Treg cells with concomitant suppression of Th17 responses. In contrast, significant increase of Th17 cells in vitreous and retina of control mouse eyes was accompanied by severe choroiditis, massive retinal-folds, and photoreceptor cell damage. These hallmark features of severe uveitis were absent in exosome-treated mice and visual impairment detected by ERG was modest compared to control mice. Absence of toxicity or alloreactivity associated with exosomes thus makes i35-Exosomes attractive therapeutic option for delivering IL-35 into CNS tissues.
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title_short	Interleukin 35-Producing Exosomes Suppress Neuroinflammation and Autoimmune Uveitis
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In this proof-of-concept study, we induced experimental autoimmune uveitis (EAU), monitored EAU progression by fundoscopy, histology, optical coherence tomography and electroretinography, and investigated whether i35-Exosomes treatment would suppress uveitis. Mice treated with i35-Exosomes developed mild EAU with low EAU scores and disease protection correlated with expansion of IL-10 and IL-35 secreting Treg cells with concomitant suppression of Th17 responses. In contrast, significant increase of Th17 cells in vitreous and retina of control mouse eyes was accompanied by severe choroiditis, massive retinal-folds, and photoreceptor cell damage. These hallmark features of severe uveitis were absent in exosome-treated mice and visual impairment detected by ERG was modest compared to control mice. 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Allergy</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Jin Kyeong Choi</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Jin Kyeong Choi</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Yingyos Jittayasothorn</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Charles E. 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Interleukin 35-Producing Exosomes Suppress Neuroinflammation and Autoimmune Uveitis

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