Costimulation and Autoimmune Diabetes in BB Rats |
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| Authors: | B C Beaudette-Zlatanova B Whalen D Zipris H Yagita J Rozing H Groen C D Benjamin T Hunig H A Drexhage M J Ansari J Leif J P Mordes D L Greiner M H Sayegh A A Rossini |
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| Institution: | Department of Medicine, The University of Massachusetts Medical School, Worcester, Massachusetts, USA;Biomedical Research Models, Inc., Worcester, Massachusetts, USA;Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan;Department of Cell Biology, Immunology Section, University of Groningen, Groningen, The Netherlands;Biogen, Inc., Boston, Massachusetts, USA;Institute for Virology and Immunobiology, University of Wurzburg, Wurzburg, Germany;Department of Immunology, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands;Transplantation Research Center, Brigham and Women's Hospital &Children's Hospital, Boston, Massachusetts, USA;Program in Molecular Medicine at The University of Massachusetts Medical School, Worcester, Massachusetts, USA |
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| Abstract: | Costimulatory signals regulate T-cell activation. To investigate the role of costimulation in autoimmunity and transplantation, we studied the BB rat model of type 1 diabetes. Diabetes-prone BB (BBDP) rats spontaneously develop disease when 55–120 days of age. We observed that two anti-CD28 monoclonal antibodies (mAb) with different functional activities completely prevented diabetes in BBDP rats. Anti-CD154 mAb delayed diabetes, whereas treatment with CTLA4-Ig or anti-CD80 mAb accelerated disease. Anti-CD86 or anti-CD134L mAbs had no effect. Diabetes resistant BB (BBDR) rats are disease-free, but >95% of them develop diabetes after treatment with polyinosinic-polycytidylic acid and an mAb that depletes Treg cells. In the induced BBDR model, anti-CD154 mAb delayed onset of diabetes, whereas CTLA4-Ig, anti-CD134L or either of the anti-CD28 mAbs had little or no effect. In contrast, blockade of the CD134-CD134L pathway was highly effective for preventing autoimmune recurrence against syngeneic islet grafts in diabetic BBDR hosts. Blockade of the CD40-CD154 pathway was also effective, but less so. These data suggest that the effectiveness of costimulation blockade in the treatment of type 1 diabetes is dependent on both the costimulatory pathway targeted and the mechanism of induction, stage, intensity and duration of the pathogenic process. |
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| Keywords: | Autoimmunity diabetes rodent tolerance transplantation |
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