Inhibition of DPP4 activity in humans establishes its in vivo role in CXCL10 post‐translational modification: prospective placebo‐controlled clinical studies. Issue 6 (14th April 2016)

• Record Type: Journal Article
• 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
• Is Part Of: EMBO molecular medicine. Volume 8:Issue 6(2016)
• Page Start: 679
• Page End: 683
• Publication Date: 2016-04-14
• Subjects: chemokines -- clinical study -- CXCL10 -- DPP4 -- post‐translational modifications; Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.15252/emmm.201506145
• Languages: English
• ISSNs: 1757-4676

Abstract

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. 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. 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.