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- Title
Costimulation and autoimmune diabetes in BB rats.
- Authors
Beaudette-Zlatanova, B C; Whalen, B; Zipris, D; Yagita, H; Rozing, J; Groen, H; Benjamin, C D; Hunig, T; Drexhage, H A; Ansari, M J; Leif, J; Mordes, J P; Greiner, D L; Sayegh, M H; Rossini, A A
- 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.
- Publication
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 2006, Vol 6, Issue 5 Pt 1, p894
- ISSN
1600-6135
- Publication type
Journal Article
- DOI
10.1111/j.1600-6143.2005.01227.x