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

Lei Ding, Conny Gysemans, Geert Stangé, Yves Heremans, Yixing Yuchi, Tatiana Takiishi, H. Korf, Marie Chintinne, Richard Carr, Henry Heimberg, Daniel Pipeleers, Chantal Mathieu

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)
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Abstract

Combining immune intervention with therapies that directly influence the functional state of the b-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 b-cell survival and possibly stimulate b-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 b-cell secretory function with resolution of destructive insulitis and preservation of b-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.
Original languageEnglish
Article numbere107935
Pages (from-to)1-13
Number of pages13
JournalPLoS ONE
Volume9
Issue number9
Publication statusPublished - 1 Sep 2014

Keywords

  • MK626
  • diabetes
  • transplantation

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