Neutralization of extracellular NAMPT (nicotinamide phosphoribosyltransferase) ameliorates experimental murine colitis.

Autor: Colombo G; Department of Pharmaceutical Sciences, University of Eastern Piedmont, A. Avogadro, 28100, Novara, Italy., Clemente N; Center for Translational Research on Autoimmune & Allergic Diseases (CAAD), Università del Piemonte Orientale, 28100, Novara, Italy., Zito A; Lab of Immunogenetics, Department of Medical Sciences, University of Turin, 10100, Turin, Italy., Bracci C; Lab of Immunogenetics, Department of Medical Sciences, University of Turin, 10100, Turin, Italy., Colombo FS; Flow Cytometry and Cell Sorting Unit, Humanitas Clinical and Research Center - IRCCS, 20089, Rozzano, MI, Italy., Sangaletti S; Molecular Immunology Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy., Jachetti E; Molecular Immunology Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy., Ribaldone DG; Department of Surgical Sciences, University of Turin, 10100, Turin, Italy., Caviglia GP; Division of Gastroenterology, Department of Medical Sciences, University of Turin, 10100, Turin, Italy., Pastorelli L; Department of Biomedical Sciences for Health, University of Milan, Milan, Italy.; Gastroenterology Unit, IRCCS Policlinico San Donato, San Donato Milanese, Italy., De Andrea M; Center for Translational Research on Autoimmune & Allergic Diseases (CAAD), Università del Piemonte Orientale, 28100, Novara, Italy.; Viral Pathogenesis Unit, Department of Public Health and Pediatric Sciences, Turin Medical School, 10126, Turin, Italy., Naviglio S; Institute for Maternal and Child Health IRCCS Burlo Garofolo, 34137, Trieste, Italy., Lucafò M; Department of Medicine, Surgery and Health Sciences, University of Trieste, 34137, Trieste, Italy., Stocco G; Department of Life Sciences, University of Trieste, 34137, Trieste, Italy., Grolla AA; Department of Pharmaceutical Sciences, University of Eastern Piedmont, A. Avogadro, 28100, Novara, Italy., Campolo M; Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina (ME), Messina, ME, Italy., Casili G; Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina (ME), Messina, ME, Italy., Cuzzocrea S; Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina (ME), Messina, ME, Italy., Esposito E; Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina (ME), Messina, ME, Italy., Malavasi F; Lab of Immunogenetics, Department of Medical Sciences, University of Turin, 10100, Turin, Italy., Genazzani AA; Department of Pharmaceutical Sciences, University of Eastern Piedmont, A. Avogadro, 28100, Novara, Italy., Porta C; Department of Pharmaceutical Sciences, University of Eastern Piedmont, A. Avogadro, 28100, Novara, Italy. chiara.porta@uniupo.it.; Center for Translational Research on Autoimmune & Allergic Diseases (CAAD), Università del Piemonte Orientale, 28100, Novara, Italy. chiara.porta@uniupo.it., Travelli C; Department of Pharmaceutical Sciences, Università degli Studi di Pavia, 27100, Pavia, Italy. cristina.travelli@unipv.it.
Jazyk: angličtina
Zdroj: Journal of molecular medicine (Berlin, Germany) [J Mol Med (Berl)] 2020 Apr; Vol. 98 (4), pp. 595-612. Date of Electronic Publication: 2020 Apr 27.
DOI: 10.1007/s00109-020-01892-0
Abstrakt: Extracellular nicotinamide phosphoribosyltransferase (eNAMPT) is increased in inflammatory bowel disease (IBD) patients, and its serum levels correlate with a worse prognosis. In the present manuscript, we show that eNAMPT serum levels are increased in IBD patients that fail to respond to anti-TNFα therapy (infliximab or adalimumab) and that its levels drop in patients that are responsive to these therapies, with values comparable with healthy subjects. Furthermore, eNAMPT administration in dinitrobenzene sulfonic acid (DNBS)-treated mice exacerbates the symptoms of colitis, suggesting a causative role of this protein in IBD. To determine the druggability of this cytokine, we developed a novel monoclonal antibody (C269) that neutralizes in vitro the cytokine-like action of eNAMPT and that reduces its serum levels in rodents. Of note, this newly generated antibody is able to significantly reduce acute and chronic colitis in both DNBS- and dextran sulfate sodium (DSS)-induced colitis. Importantly, C269 ameliorates the symptoms by reducing pro-inflammatory cytokines. Specifically, in the lamina propria, a reduced number of inflammatory monocytes, neutrophils, Th1, and cytotoxic T lymphocytes are found upon C269 treatment. Our data demonstrate that eNAMPT participates in IBD and, more importantly, that eNAMPT-neutralizing antibodies are endowed with a therapeutic potential in IBD. KEY MESSAGES: What are the new findings? Higher serum eNAMPT levels in IBD patients might decrease response to anti-TNF therapy. The cytokine-like activity of eNAMPT may be neutralized with a monoclonal antibody. Neutralization of eNAMPT ameliorates acute and chronic experimental colitis. Neutralization of eNAMPT limits the expression of IBD inflammatory signature. Neutralization of eNAMPT impairs immune cell infiltration in lamina propria.
Databáze: MEDLINE
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