Carboxylesterase-1 Assisted Targeting of HDAC Inhibitors to Mononuclear Myeloid Cells in Inflammatory Bowel Disease.

Autor:	Elfiky AMI; Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology & Metabolism, Amsterdam University Medical Centers, Amsterdam, The Netherlands.; Immunology Research Unit, GSK Medicines Research Centre, Stevenage, UK., Ghiboub M; Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology & Metabolism, Amsterdam University Medical Centers, Amsterdam, The Netherlands.; Immunology Research Unit, GSK Medicines Research Centre, Stevenage, UK., Li Yim AYF; Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology & Metabolism, Amsterdam University Medical Centers, Amsterdam, The Netherlands.; Immunology Research Unit, GSK Medicines Research Centre, Stevenage, UK.; Department of Clinical Genetics, Amsterdam Reproduction & Development, Amsterdam University Medical Centers, Amsterdam, The Netherlands., Hageman IL; Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology & Metabolism, Amsterdam University Medical Centers, Amsterdam, The Netherlands., Verhoeff J; Department of Molecular Cell Biology & Immunology, Amsterdam Infection & Immunity Institute and Cancer Center Amsterdam, Amsterdam University Medical Centers, Amsterdam, The Netherlands., de Krijger M; Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology & Metabolism, Amsterdam University Medical Centers, Amsterdam, The Netherlands., van Hamersveld PHP; Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology & Metabolism, Amsterdam University Medical Centers, Amsterdam, The Netherlands., Welting O; Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology & Metabolism, Amsterdam University Medical Centers, Amsterdam, The Netherlands., Admiraal I; Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology & Metabolism, Amsterdam University Medical Centers, Amsterdam, The Netherlands., Rahman S; Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology & Metabolism, Amsterdam University Medical Centers, Amsterdam, The Netherlands., Garcia-Vallejo JJ; Department of Molecular Cell Biology & Immunology, Amsterdam Infection & Immunity Institute and Cancer Center Amsterdam, Amsterdam University Medical Centers, Amsterdam, The Netherlands., Wildenberg ME; Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology & Metabolism, Amsterdam University Medical Centers, Amsterdam, The Netherlands., Tomlinson L; Discovery DMPK, IVIVT, GSK Medicines Research Centre, Stevenage, UK., Gregory R; Discovery DMPK, IVIVT, GSK Medicines Research Centre, Stevenage, UK., Rioja I; Immunology Research Unit, GSK Medicines Research Centre, Stevenage, UK., Prinjha RK; Immunology Research Unit, GSK Medicines Research Centre, Stevenage, UK., Furze RC; Immunology Research Unit, GSK Medicines Research Centre, Stevenage, UK., Lewis HD; Immunology Research Unit, GSK Medicines Research Centre, Stevenage, UK., Mander PK; Immunology Research Unit, GSK Medicines Research Centre, Stevenage, UK., Heinsbroek SEM; Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology & Metabolism, Amsterdam University Medical Centers, Amsterdam, The Netherlands., Bell MJ; Immunology Research Unit, GSK Medicines Research Centre, Stevenage, UK., de Jonge WJ; Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology & Metabolism, Amsterdam University Medical Centers, Amsterdam, The Netherlands.; Department of Surgery, University of Bonn, Bonn, Germany.
Jazyk:	angličtina
Zdroj:	Journal of Crohn's & colitis [J Crohns Colitis] 2022 May 10; Vol. 16 (4), pp. 668-681.
DOI:	10.1093/ecco-jcc/jjab176
Abstrakt:	Background and Aims: Histone deacetylase inhibitors [HDACi] exert potent anti-inflammatory effects. Because of the ubiquitous expression of HDACs, clinical utility of HDACi is limited by off-target effects. Esterase-sensitive motif [ESM] technology aims to deliver ESM-conjugated compounds to human mononuclear myeloid cells, based on their expression of carboxylesterase 1 [CES1]. This study aims to investigate utility of an ESM-tagged HDACi in inflammatory bowel disease [IBD]. Methods: CES1 expression was assessed in human blood, in vitro differentiated macrophage and dendritic cells, and Crohn's disease [CD] colon mucosa, by mass cytometry, quantitative polymerase chain reaction [PCR], and immunofluorescence staining, respectively. ESM-HDAC528 intracellular retention was evaluated by mass spectrometry. Clinical efficacy of ESM-HDAC528 was tested in dextran sulphate sodium [DSS]-induced colitis and T cell transfer colitis models using transgenic mice expressing human CES1 under the CD68 promoter. Results: CES1 mRNA was highly expressed in human blood CD14+ monocytes, in vitro differentiated and lipopolysaccharide [LPS]-stimulated macrophages, and dendritic cells. Specific hydrolysis and intracellular retention of ESM-HDAC528 in CES1+ cells was demonstrated. ESM-HDAC528 inhibited LPS-stimulated IL-6 and TNF-α production 1000 times more potently than its control, HDAC800, in CES1high monocytes. In healthy donor peripheral blood, CES1 expression was significantly higher in CD14++CD16- monocytes compared with CD14+CD16++ monocytes. In CD-inflamed colon, a higher number of mucosal CD68+ macrophages expressed CES1 compared with non-inflamed mucosa. In vivo, ESM-HDAC528 reduced monocyte differentiation in the colon and significantly improved colitis in a T cell transfer model, while having limited potential in ameliorating DSS-induced colitis. Conclusions: We demonstrate that monocytes and inflammatory macrophages specifically express CES1, and can be preferentially targeted by ESM-HDAC528 to achieve therapeutic benefit in IBD. (© The Author(s) 2021. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)
Databáze:	MEDLINE
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