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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| Affiliation: | 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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