title: Combining MK626, a novel DPP-4 inhibitor, and low-dose monoclonal CD3 antibody for stable remission of new-onset diabetes in mice.
abstract: Combining immune intervention with therapies that directly influence the functional state of the β-cells is an interesting strategy in type 1 diabetes cure. Dipeptidyl peptidase-4 (DPP-4) inhibitors elevate circulating levels of active incretins, which have been reported to enhance insulin secretion and synthesis, can support β-cell survival and possibly stimulate β-cell proliferation and neogenesis. In the current study, we demonstrate that the DPP-4 inhibitor MK626, which has appropriate pharmacokinetics in mice, preceded by a short-course of low-dose anti-CD3 generated durable diabetes remission in new-onset diabetic non-obese diabetic (NOD) mice. Induction of remission involved recovery of β-cell secretory function with resolution of destructive insulitis and preservation of β-cell volume/mass, along with repair of the islet angioarchitecture via SDF-1- and VEGF-dependent actions. Combination therapy temporarily reduced the CD4-to-CD8 distribution in spleen although not in pancreatic draining lymph nodes (PLN) and increased the proportion of effector/memory T cells as did anti-CD3 alone. In contrast, only combination therapy amplified Foxp3+ regulatory T cells in PLN and locally in pancreas. These findings open new opportunities for the treatment of new-onset type 1 diabetes by introducing DPP-4 inhibitors in human CD3-directed clinical trials.
authors.affiliation: Laboratory of Clinical and Experimental Endocrinology, Campus Gasthuisberg O&N1, Faculty of Medicine, Katholieke Universiteit Leuven (KU LEUVEN), Leuven, Belgium.
authors.forename: Lei
authors.initials: L
authors.lastname: Ding
authors.affiliation: Laboratory of Clinical and Experimental Endocrinology, Campus Gasthuisberg O&N1, Faculty of Medicine, Katholieke Universiteit Leuven (KU LEUVEN), Leuven, Belgium.
authors.forename: Conny A
authors.initials: CA
authors.lastname: Gysemans
authors.affiliation: Laboratory of Diabetes Pathology and Therapy, Diabetes Research Center, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
authors.forename: Geert
authors.initials: G
authors.lastname: Stangé
authors.affiliation: Laboratory of Beta Cell Neogenesis (BENE), Diabetes Research Center, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
authors.forename: Yves
authors.initials: Y
authors.lastname: Heremans
authors.affiliation: Laboratory of Beta Cell Neogenesis (BENE), Diabetes Research Center, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
authors.forename: Yixing
authors.initials: Y
authors.lastname: Yuchi
authors.affiliation: Laboratory of Clinical and Experimental Endocrinology, Campus Gasthuisberg O&N1, Faculty of Medicine, Katholieke Universiteit Leuven (KU LEUVEN), Leuven, Belgium.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Takiishi
authors.affiliation: Laboratory of Clinical and Experimental Endocrinology, Campus Gasthuisberg O&N1, Faculty of Medicine, Katholieke Universiteit Leuven (KU LEUVEN), Leuven, Belgium.
authors.forename: Hannelie
authors.initials: H
authors.lastname: Korf
authors.affiliation: Laboratory of Diabetes Pathology and Therapy, Diabetes Research Center, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
authors.forename: Marie
authors.initials: M
authors.lastname: Chintinne
authors.affiliation: MSD A/S, Ballerup, Denmark.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Carr
authors.affiliation: Laboratory of Beta Cell Neogenesis (BENE), Diabetes Research Center, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
authors.forename: Harry
authors.initials: H
authors.lastname: Heimberg
authors.affiliation: Laboratory of Diabetes Pathology and Therapy, Diabetes Research Center, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
authors.forename: Daniel
authors.initials: D
authors.lastname: Pipeleers
authors.affiliation: Laboratory of Clinical and Experimental Endocrinology, Campus Gasthuisberg O&N1, Faculty of Medicine, Katholieke Universiteit Leuven (KU LEUVEN), Leuven, Belgium.
authors.forename: Chantal
authors.initials: C
authors.lastname: Mathieu
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D017252:CD3 Complex / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D006224:Cricetinae; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D010179:Pancreas / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D012074:Remission Induction; D013154:Spleen / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents