title: Inhibition of DPP4 activity in humans establishes its in vivo role in CXCL10 post-translational modification: prospective placebo-controlled clinical studies.
abstract: Biochemical experiments, animal models, and observational studies in humans all support a role of dipeptidyl peptidase 4 (DPP4) in the N-terminal truncation of CXCL10, which results in the generation of an antagonist form of the chemokine that limits T-cell and NK cell migration. Motivated by the ability to regulate lymphocyte trafficking in vivo, we conducted two prospective clinical trials to test the effects of DPP4 inhibition on CXCL10 processing in healthy donors and in chronic hepatitis C patients, a disease in which DPP4 levels are found to be elevated. Participants were treated daily with 100 mg sitagliptin, a clinically approved DPP4 inhibitor. Plasma samples were analyzed using an ultrasensitive single-molecule assay (Simoa) to distinguish the full-length CXCL101-77 from the NH2-truncated CXCL103-77, as compared to the total CXCL10 levels. Sitagliptin treatment resulted in a significant decrease in CXCL103-77 concentration, a reciprocal increase in CXCL101-77, with only minimal effects on total levels of the chemokine. These data provide the first direct evidence that in vivo DPP4 inhibition in humans can preserve the bioactive form of CXCL10, offering new therapeutic opportunities for DPP4 inhibitors.
authors.affiliation: The Laboratory of Dendritic Cell Immunobiology, Institut Pasteur, Paris, France INSERM U818, Paris, France.
authors.forename: Jérémie
authors.initials: J
authors.lastname: Decalf
authors.affiliation: Diabetes Endocrinology and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Kristin V
authors.initials: KV
authors.lastname: Tarbell
authors.affiliation: The Laboratory of Dendritic Cell Immunobiology, Institut Pasteur, Paris, France INSERM U818, Paris, France.
authors.forename: Armanda
authors.initials: A
authors.lastname: Casrouge
authors.affiliation: Diabetes Endocrinology and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Price
authors.affiliation: Diabetes Endocrinology and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Grace
authors.initials: G
authors.lastname: Linder
authors.affiliation: Center for Human Immunology, Institut Pasteur, Paris, France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Mottez
authors.affiliation: Département d'Hépatologie, AP-HP, Hôpital Cochin, Université Paris Descartes, INSERM UMS20, Institut Pasteur, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Sultanik
authors.affiliation: Département d'Hépatologie, AP-HP, Hôpital Cochin, Université Paris Descartes, INSERM UMS20, Institut Pasteur, Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Mallet
authors.affiliation: Département d'Hépatologie, AP-HP, Hôpital Cochin, Université Paris Descartes, INSERM UMS20, Institut Pasteur, Paris, France.
authors.forename: Stanislas
authors.initials: S
authors.lastname: Pol
authors.affiliation: The Laboratory of Dendritic Cell Immunobiology, Institut Pasteur, Paris, France INSERM U818, Paris, France Center for Human Immunology, Institut Pasteur, Paris, France darragh.duffy@pasteur.fr albertm@pasteur.fr.
authors.forename: Darragh
authors.identifier: 0000-0002-8875-2308
authors.initials: D
authors.lastname: Duffy
authors.affiliation: The Laboratory of Dendritic Cell Immunobiology, Institut Pasteur, Paris, France INSERM U818, Paris, France Center for Human Immunology, Institut Pasteur, Paris, France Department of Cancer Immunotherapy, Genentech, South San Francisco, CA, USA darragh.duffy@pasteur.fr albertm@pasteur.fr.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Albert
mesh_terms: D054357:Chemokine CXCL10 / Q000097:blood / Q000378:metabolism*; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage*; D064368:Healthy Volunteers; D019698:Hepatitis C, Chronic / Q000473:pathology; D006801:Humans; D010919:Placebos / Q000008:administration & dosage; D011446:Prospective Studies; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D000068900:Sitagliptin Phosphate / Q000008:administration & dosage*
chemical_list: C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D054873:Dipeptidyl-Peptidase IV Inhibitors; D010919:Placebos; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D000068900:Sitagliptin Phosphate
keywords: CXCL10; DPP4; chemokines; clinical study; post‐translational modifications