title: Synergistic reversal of type 1 diabetes in NOD mice with anti-CD3 and interleukin-1 blockade: evidence of improved immune regulation.
abstract: Inflammatory cytokines are involved in autoimmune diabetes: among the most prominent is interleukin (IL)-1β. We postulated that blockade of IL-1β 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-1β 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)-γ 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-γ, 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.
authors: Department of Immunobiology and Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
authors: Vitaly
authors: V
authors: Ablamunits
authors: Octavian
authors: O
authors: Henegariu
authors: Jakob Bondo
authors: JB
authors: Hansen
authors: Lynn
authors: L
authors: Opare-Addo
authors: Paula
authors: P
authors: Preston-Hurlburt
authors: Pere
authors: P
authors: Santamaria
authors: Thomas
authors: T
authors: Mandrup-Poulsen
authors: Kevan C
authors: KC
authors: Herold
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D017252:CD3 Complex / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000628:therapy*; D004338:Drug Combinations; D004357:Drug Synergism; D005260:Female; D055633:Immune System Phenomena / Q000187:drug effects* / Q000502:physiology; D007167:Immunotherapy / Q000379:methods; D053590:Interleukin 1 Receptor Antagonist Protein / Q000627:therapeutic use*; D007375:Interleukin-1 / Q000037:antagonists & inhibitors*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D012074:Remission Induction / Q000379:methods
chemical_list: D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D004338:Drug Combinations; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1