The combination of anti-NKG2D and CTLA-4 Ig therapy prolongs islet allograft survival in a murine model

Abstract

Islet transplantation is an effective means of treating severe type 1 diabetes in patients with life-threatening hypoglycemia. Improvements in glycemic control with correction of HbA1C enhance quality of life irrespective of insulin independence. By antagonizing the Natural Killer Group 2, member D (NKG2D) receptor expression on NK and CD8+ T cells, in combination with blocking CTLA-4 binding sites, we demonstrate a significant delay of graft rejection in islet allotransplant. Anti-NKG2D combined with CTLA-4 Ig (n=15) results in prolonged allograft survival, with 84.6±10% of the recipients displaying insulin independence compared to controls (n=10, p<0.001). The effect of combination therapy on graft survival is superior to treatments alone (CTLA-4 Ig vs. combination p=0.024, anti-NKG2D vs. combination p<0.001) indicating an interaction between these pathways. In addition, combination treatment also improves glucose tolerance when compared to controls (n=10, p=0.018). Histologically, NKG2D+ cells were significantly decreased within the allograft after 7 days of combination treatment (n=6, p=0.029). T cell proliferation was significantly reduced with anti-NKG2D therapy and CD8+ T cell daughter fractions were also significantly decreased with mAb and combination treatment when measured by in vitro mixed lymphocyte reaction (n=5, p=0.015, p=0.005 and p=0.048). These results demonstrate that inhibition of NKG2D receptors and costimulatory pathways enhance islet allograft survival. Antagonizing the Natural Killer Group 2, member D receptor expression on NK and CD8+ T cells, in combination with blocking CTLA-4 binding sites, significantly prolongs islet allograft survival.