Open AccessInhibition of DPP 4 activity in humans establishes its in vivo role in CXCL 10 post‐translational modification: prospective placebo‐controlled clinical studies
Author(s) -
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
Publication year - 2016
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201506145
Subject(s) - in vivo , chemistry , posttranslational modification , pharmacology , medicine , enzyme , biochemistry , biology , genetics
Biochemical experiments, animal models, and observational studies in humans all support a role of dipeptidyl peptidase 4 ( DPP 4) in the N‐terminal truncation of CXCL 10, 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 DPP 4 inhibition on CXCL 10 processing in healthy donors and in chronic hepatitis C patients, a disease in which DPP 4 levels are found to be elevated. Participants were treated daily with 100 mg sitagliptin, a clinically approved DPP 4 inhibitor. Plasma samples were analyzed using an ultrasensitive single‐molecule assay (Simoa) to distinguish the full‐length CXCL 10 1–77 from the NH 2 ‐truncated CXCL 10 3–77 , as compared to the total CXCL 10 levels. Sitagliptin treatment resulted in a significant decrease in CXCL 10 3–77 concentration, a reciprocal increase in CXCL 10 1–77 , with only minimal effects on total levels of the chemokine. These data provide the first direct evidence that in vivo DPP 4 inhibition in humans can preserve the bioactive form of CXCL 10, offering new therapeutic opportunities for DPP 4 inhibitors.