Costimulation and autoimmune diabetes in BB rats

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

*Corresponding author for this work

Research output: Contribution to journalArticle

18 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)894-902
Number of pages9
JournalAmerican Journal of Transplantation
Volume6
Issue number5 I
DOIs
Publication statusPublished - May 1 2006

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Keywords

  • Autoimmunity
  • Diabetes
  • Rodent
  • Tolerance
  • Transplantation

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

Cite this

Beaudette-Zlatanova, B. C., Whalen, B., Zipris, D., Yagita, H., Rozing, J., Groen, H., ... Rossini, A. A. (2006). Costimulation and autoimmune diabetes in BB rats. American Journal of Transplantation, 6(5 I), 894-902. https://doi.org/10.1111/j.1600-6143.2005.01227.x