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Synergistic reversal of type 1 diabetes in NOD mice with anti-CD3 and interleukin-1 blockade: evidence of improved immune regulation

Publikation: Bidrag til tidsskriftTidsskriftartikel

  • Vitaly Ablamunits
  • Octavian Henegariu
  • Jakob Bondo Hansen
  • Lynn Opare-Addo
  • Paula Preston-Hurlburt
  • Pere Santamaria
  • Mandrup-Poulsen, Thomas
  • Kevan C Herold
Inflammatory cytokines are involved in autoimmune diabetes: among the most prominent is interleukin (IL)-1ß. We postulated that blockade of IL-1ß would modulate the effects of anti-CD3 monoclonal antibody (mAb) in treating diabetes in NOD mice. To test this, we treated hyperglycemic NOD mice with F(ab')(2) fragments of anti-CD3 mAb with or without IL-1 receptor antagonist (IL-1RA), or anti-IL-1ß mAb. We studied the reversal of diabetes and effects of treatment on the immune system. Mice that received a combination of anti-CD3 mAb with IL-1RA showed a more rapid rate of remission of diabetes than mice treated with anti-CD3 mAb or IL-1RA alone. Combination-treated mice had increased IL-5, IL-4, and interferon (IFN)-¿ levels in circulation. There were reduced pathogenic NOD-relevant V7 peptide-V7(+) T cells in the pancreatic lymph nodes. Their splenocytes secreted more IL-10, had increased arginase expression in macrophages and dendritic cells, and had delayed adoptive transfer of diabetes. After 1 month, there were increased concentrations of IgG1 isotype antibodies and reduced intrapancreatic expression of IFN-¿, IL-6, and IL-17 despite normal splenocyte cytokine secretion. These studies indicate that the combination of anti-CD3 mAb with IL-1RA is synergistic in reversal of diabetes through a combination of mechanisms. The combination causes persistent remission from islet inflammation.
OriginalsprogEngelsk
TidsskriftDiabetes
Vol/bind61
Udgave nummer1
Sider (fra-til)145-54
Antal sider10
ISSN0012-1797
DOI
StatusUdgivet - 2012

ID: 38412243