TY - JOUR

T1 - Synergistic reversal of type 1 diabetes in NOD mice with anti-CD3 and interleukin-1 blockade

T2 - evidence of improved immune regulation

AU - Ablamunits, Vitaly

AU - Henegariu, Octavian

AU - Hansen, Jakob Bondo

AU - Opare-Addo, Lynn

AU - Preston-Hurlburt, Paula

AU - Santamaria, Pere

AU - Mandrup-Poulsen, Thomas

AU - Herold, Kevan C

PY - 2012

Y1 - 2012

N2 - 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.

AB - 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.

KW - Animals

KW - Antibodies, Monoclonal

KW - Antigens, CD3

KW - Diabetes Mellitus, Type 1

KW - Drug Combinations

KW - Drug Synergism

KW - Female

KW - Immune System Processes

KW - Immunotherapy

KW - Interleukin 1 Receptor Antagonist Protein

KW - Interleukin-1

KW - Mice

KW - Mice, Inbred NOD

KW - Mice, SCID

KW - Remission Induction

U2 - 10.2337/db11-1033

DO - 10.2337/db11-1033

M3 - Journal article

C2 - 22043003

VL - 61

SP - 145

EP - 154

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 1

ER -