Costimulation and Autoimmune Diabetes in BB Rats

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 polyinosinicpolycytidylic 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 Dr. Christopher D. Benjamin is an employee of Biogen, Inc., which has a financial interest in this work. Drs. Rossini, Mordes and Greiner hold intellectual property rights.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.

Amplification of Regulatory T Cells Using a CD28 Superagonist Reduces Brain Damage After Ischemic Stroke in Mice

“…In the present study, we tested a more powerful and less pleiotropic approach of boosting Treg compared with histone deacetylase inhibition-stimulation with the CD28SA. Similar to previous studies in healthy mice 13 and various disease models, [15][16][17][18][19] CD28SA substantially increased the number of Treg in the periphery as well as in the brain. CD28SA …”

“…13,14 Application of CD28SA in vivo effectively expands and potently activates polyclonal Treg. 13 In a variety of disease models, CD28SA reduced autoimmune reactions, [15][16][17] graft rejection, 18 and inflammation.…”

Foxp3-expressing Regulatory T Cells Expanded With CD28 Superagonist Antibody Can Prevent Rat Cardiac Allograft Rejection

“…8 Recently, studies in rodent autoimmune disease models have shown efficacy of supCD28 MAb treatment in the prevention of experimental autoimmune neuritis and experimental autoimmune encephalomyelitis with marked reduction of infiltrating cells and interferon (IFN)-␥ production, 9 adjuvant arthritis with amelioration of Th1/Th2 cell balance and induction of high IL-10 expression in synovia, 10 and in the Type 1 diabetes BB rat model with an increase of CD4 ϩ CD25 ϩ T-cell frequency. 11 In this study we show that in vivo application of supCD28 MAb to Lewis rats causes preferential expansion of Foxp3-expressing Treg cells over conventional T cells, and maintains not only their phenotype but also their potent regulatory functions against T-cell proliferation in response to mitogens, antibodies and allostimulation in vitro. Furthermore, using a full MHC-mismatch rat heterotopic heart transplantation model, we found that supCD28 MAb preferentially expands naturally occurring Treg (nTreg) cells and recruits these nTreg cells to the grafts, resulting in significant prolongation of cardiac graft survival.…”

Prolonged exclusive breastfeeding reduces autoimmune diabetes incidence and increases regulatory T‐cell frequency in bio‐breeding diabetes‐prone rats

“…It was shown that restoration of the defect in regulatory T-cell function in BBDP rats by adoptive transfer with functional regulatory T cells from autoimmune diabetes-resistant BB rats, prevents autoimmune diabetes development [16][17][18]. Moreover, also in vivo expansion of Tregs in BBDP rats by super-agonistic αCD28 antibodies completely prevented autoimmune diabetes development [22].…”