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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.
AuthorsR Pawlick, B Gala-Lopez, A R Pepper, M McCall, O Ziff, A M J Shapiro
JournalAmerican journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons (Am J Transplant) Vol. 14 Issue 10 Pg. 2367-74 (Oct 2014) ISSN: 1600-6143 [Electronic] United States
PMID25179027 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright© Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.
Chemical References
  • CTLA-4 Antigen
  • Immunoglobulins
  • Klrk1 protein, mouse
  • NK Cell Lectin-Like Receptor Subfamily K
Topics
  • Animals
  • CTLA-4 Antigen (immunology)
  • Graft Survival (immunology)
  • Immunoglobulins (administration & dosage)
  • Islets of Langerhans Transplantation
  • Lymphocyte Culture Test, Mixed
  • Mice
  • Mice, Inbred C57BL
  • Models, Animal
  • NK Cell Lectin-Like Receptor Subfamily K (immunology)

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