CSL362 potently and specifically depletes pDCs in vitro and ablates SLE-immune complex-induced IFN responses
Summary: Systemic lupus erythematosus (SLE) is an autoimmune disease with significant morbidity and mortality. Type I interferon (IFN) drives SLE pathology and plasmacytoid dendritic cells (pDCs) are potent producers of IFN; however, the specific effects of pDC depletion have not been demonstrated....
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| Format: | Article |
| Language: | English |
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Elsevier
2023-07-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004223012506 |
| _version_ | 1797774582231334912 |
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| author | Katherine A. Monaghan Alberta Hoi Cristina Gamell Tsin Yee Tai Bryan Linggi Jarrat Jordan Matteo Cesaroni Takahiro Sato Milica Ng Shereen Oon Jacqueline Benson Ian Wicks Eric Morand Nicholas Wilson |
| author_facet | Katherine A. Monaghan Alberta Hoi Cristina Gamell Tsin Yee Tai Bryan Linggi Jarrat Jordan Matteo Cesaroni Takahiro Sato Milica Ng Shereen Oon Jacqueline Benson Ian Wicks Eric Morand Nicholas Wilson |
| author_sort | Katherine A. Monaghan |
| collection | DOAJ |
| description | Summary: Systemic lupus erythematosus (SLE) is an autoimmune disease with significant morbidity and mortality. Type I interferon (IFN) drives SLE pathology and plasmacytoid dendritic cells (pDCs) are potent producers of IFN; however, the specific effects of pDC depletion have not been demonstrated. We show CD123 was highly expressed on pDCs and the anti-CD123 antibody CSL362 potently depleted pDCs in vitro. CSL362 pre-treatment abrogated the induction of IFNα and IFN-induced gene transcription following stimulation with SLE patient-derived serum or immune complexes. RNA transcripts induced in pDCs by ex vivo stimulation with TLR ligands were reflected in gene expression profiles of SLE blood, and correlated with disease severity. TLR ligand-induced protein production by SLE patient peripheral mononuclear cells was abrogated by CSL362 pre-treatment including proteins over expressed in SLE patient serum. These findings implicate pDCs as key drivers in the cellular activation and production of soluble factors seen in SLE. |
| first_indexed | 2024-03-12T22:22:14Z |
| format | Article |
| id | doaj.art-eb8684484db641f3996c7933c3238670 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-03-12T22:22:14Z |
| publishDate | 2023-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-eb8684484db641f3996c7933c32386702023-07-23T04:55:49ZengElsevieriScience2589-00422023-07-01267107173CSL362 potently and specifically depletes pDCs in vitro and ablates SLE-immune complex-induced IFN responsesKatherine A. Monaghan0Alberta Hoi1Cristina Gamell2Tsin Yee Tai3Bryan Linggi4Jarrat Jordan5Matteo Cesaroni6Takahiro Sato7Milica Ng8Shereen Oon9Jacqueline Benson10Ian Wicks11Eric Morand12Nicholas Wilson13Research and Development, CSL Limited, Melbourne, VIC 3010, Australia; Corresponding authorCentre for Inflammatory Disease, School of Clinical Sciences, Monash University, Melbourne, VIC 3168, Australia; Monash Health, Clayton, VIC 3168, AustraliaResearch and Development, CSL Limited, Melbourne, VIC 3010, AustraliaResearch and Development, CSL Limited, Melbourne, VIC 3010, AustraliaJanssen Research and Development LLC, Spring House, PA 19477, USAJanssen Research and Development LLC, Spring House, PA 19477, USAJanssen Research and Development LLC, Spring House, PA 19477, USAJanssen Research and Development LLC, Spring House, PA 19477, USAResearch and Development, CSL Limited, Melbourne, VIC 3010, AustraliaThe Walter and Eliza Hall Institute, Parkville, VIC 3052, Australia; The Royal Melbourne Hospital, Parkville, VIC 3050, Australia; The University of Melbourne Parkville, Parkville, VIC 3010, AustraliaJanssen Research and Development LLC, Spring House, PA 19477, USAThe Walter and Eliza Hall Institute, Parkville, VIC 3052, Australia; The Royal Melbourne Hospital, Parkville, VIC 3050, Australia; The University of Melbourne Parkville, Parkville, VIC 3010, AustraliaCentre for Inflammatory Disease, School of Clinical Sciences, Monash University, Melbourne, VIC 3168, Australia; Monash Health, Clayton, VIC 3168, AustraliaResearch and Development, CSL Limited, Melbourne, VIC 3010, AustraliaSummary: Systemic lupus erythematosus (SLE) is an autoimmune disease with significant morbidity and mortality. Type I interferon (IFN) drives SLE pathology and plasmacytoid dendritic cells (pDCs) are potent producers of IFN; however, the specific effects of pDC depletion have not been demonstrated. We show CD123 was highly expressed on pDCs and the anti-CD123 antibody CSL362 potently depleted pDCs in vitro. CSL362 pre-treatment abrogated the induction of IFNα and IFN-induced gene transcription following stimulation with SLE patient-derived serum or immune complexes. RNA transcripts induced in pDCs by ex vivo stimulation with TLR ligands were reflected in gene expression profiles of SLE blood, and correlated with disease severity. TLR ligand-induced protein production by SLE patient peripheral mononuclear cells was abrogated by CSL362 pre-treatment including proteins over expressed in SLE patient serum. These findings implicate pDCs as key drivers in the cellular activation and production of soluble factors seen in SLE.http://www.sciencedirect.com/science/article/pii/S2589004223012506Health sciencesImmunologyPathophysiology |
| spellingShingle | Katherine A. Monaghan Alberta Hoi Cristina Gamell Tsin Yee Tai Bryan Linggi Jarrat Jordan Matteo Cesaroni Takahiro Sato Milica Ng Shereen Oon Jacqueline Benson Ian Wicks Eric Morand Nicholas Wilson CSL362 potently and specifically depletes pDCs in vitro and ablates SLE-immune complex-induced IFN responses iScience Health sciences Immunology Pathophysiology |
| title | CSL362 potently and specifically depletes pDCs in vitro and ablates SLE-immune complex-induced IFN responses |
| title_full | CSL362 potently and specifically depletes pDCs in vitro and ablates SLE-immune complex-induced IFN responses |
| title_fullStr | CSL362 potently and specifically depletes pDCs in vitro and ablates SLE-immune complex-induced IFN responses |
| title_full_unstemmed | CSL362 potently and specifically depletes pDCs in vitro and ablates SLE-immune complex-induced IFN responses |
| title_short | CSL362 potently and specifically depletes pDCs in vitro and ablates SLE-immune complex-induced IFN responses |
| title_sort | csl362 potently and specifically depletes pdcs in vitro and ablates sle immune complex induced ifn responses |
| topic | Health sciences Immunology Pathophysiology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004223012506 |
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