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

V Ablamunits, O Henegariu, JB Hansen… - Diabetes, 2012 - Am Diabetes Assoc
V Ablamunits, O Henegariu, JB Hansen, L Opare-Addo, P Preston-Hurlburt, P Santamaria
Diabetes, 2012Am Diabetes Assoc
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 …
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.
Am Diabetes Assoc