Combining MK626, a novel DPP-4 inhibitor, and low-dose monoclonal CD3 antibody for stable remission of new-onset diabetes in mice

• Published in: PloS one Vol. 9; no. 9; p. e107935
• Main Authors: Ding, Lei, Gysemans, Conny A, Stangé, Geert, Heremans, Yves, Yuchi, Yixing, Takiishi, Tatiana, Korf, Hannelie, Chintinne, Marie, Carr, Richard D, Heimberg, Harry, Pipeleers, Daniel, Mathieu, Chantal
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 30.09.2014; Public Library of Science (PLoS)
• Subjects: Adenosine; Animals; Antibodies, Monoclonal - pharmacology; Biology and Life Sciences; CD3 antigen; CD3 Complex - genetics; CD3 Complex - immunology; CD4 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - pathology; Cell proliferation; Cell size; Cell survival; Clinical trials; Cricetinae; Cytokines; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 1 - drug therapy; Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - pathology; Dipeptidyl-peptidase IV; Dipeptidyl-Peptidase IV Inhibitors - pharmacology; Drainage; Drug dosages; Drug Synergism; Drug Therapy, Combination; Effector cells; Endocrinology; Enzymes; Foxp3 protein; Glucose; Hyperglycemia; Hypoglycemic Agents - pharmacology; Immunological memory; Immunoregulation; Immunotherapy; Inhibitors; Insulin; Insulin secretion; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - immunology; Insulin-Secreting Cells - pathology; Insulitis; Laboratories; Lymph nodes; Lymph Nodes - drug effects; Lymph Nodes - immunology; Lymph Nodes - pathology; Lymphocytes; Lymphocytes T; Medical research; Medicine; Medicine and Health Sciences; Memory cells; Mice; Mice, Inbred NOD; Pancreas; Pancreas - drug effects; Pancreas - immunology; Pancreas - pathology; Pathology; Peptidase; Peptides; Pharmacokinetics; Pharmacology; Pharmacy; Preservation; Remission (Medicine); Remission Induction; Rodents; Spleen; Spleen - drug effects; Spleen - immunology; Spleen - pathology; Studies; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - pathology; Therapy; Vascular endothelial growth factor
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0107935

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.