Inhibition of DPP4 activity in humans establishes its in vivo role in CXCL10 post‐translational modification: prospective placebo‐controlled clinical studies

• Published in: EMBO molecular medicine Vol. 8; no. 6; pp. 679 - 683
• Main Authors: Decalf, Jérémie, Tarbell, Kristin V, Casrouge, Armanda, Price, Jeffrey D, Linder, Grace, Mottez, Estelle, Sultanik, Philippe, Mallet, Vincent, Pol, Stanislas, Duffy, Darragh, Albert, Matthew L
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2016; Wiley Open Access; John Wiley and Sons Inc; Springer Nature
• Subjects: Chemokine CXCL10 - blood; Chemokine CXCL10 - metabolism; chemokines; clinical study; CXCL10; Dipeptidyl Peptidase 4 - metabolism; Dipeptidyl-Peptidase IV Inhibitors - administration & dosage; DPP4; EMBO23; EMBO28; EMBO31; Healthy Volunteers; Hepatitis C, Chronic - pathology; Humans; Immunology; Life Sciences; Placebos - administration & dosage; post‐translational modifications; Prospective Studies; Protein Processing, Post-Translational; Proteolysis; Sitagliptin Phosphate - administration & dosage; clinical study; DPP4; post‐translational modifications; CXCL10; chemokines
• ISSN: 1757-4676; 1757-4684
• DOI: 10.15252/emmm.201506145

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 CXCL10 1–77 from the NH 2 ‐truncated CXCL10 3–77 , as compared to the total CXCL10 levels. Sitagliptin treatment resulted in a significant decrease in CXCL10 3–77 concentration, a reciprocal increase in CXCL10 1–77 , 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. Synopsis The N‐terminal truncation of CXCL10 by DPP4 results in the generation of an antagonist form of the chemokine that limits T‐cell and NK cell migration. This study shows for the first time that in vivo DPP4 inhibition in humans can preserve the bioactive form of CXCL10. Sitagliptin, an FDA‐approved DPP4 inhibitor for the treatment of type 2 diabetes, resulted in a decrease in the concentration of antagonist CXCL10 and a reciprocal increase in levels of the agonist form. Sitagliptin was effective in healthy subjects as well as in chronic HCV patients who have elevated levels of DPP4 and CXCL10. These results open new perspectives in the use of DPP4 inhibitors as therapeutic immune modulators. Graphical Abstract The N‐terminal truncation of CXCL10 by DPP4 results in the generation of an antagonist form of the chemokine that limits T‐cell and NK cell migration. This study shows for the first time that in vivo DPP4 inhibition in humans can preserve the bioactive form of CXCL10.