title: 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.
authors.affiliation: Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Pawlick
authors.forename: B
authors.initials: B
authors.lastname: Gala-Lopez
authors.forename: A R
authors.initials: AR
authors.lastname: Pepper
authors.forename: M
authors.initials: M
authors.lastname: McCall
authors.forename: O
authors.initials: O
authors.lastname: Ziff
authors.forename: A M J
authors.initials: AM
authors.lastname: Shapiro
mesh_terms: D000818:Animals; D060908:CTLA-4 Antigen / Q000276:immunology*; D006085:Graft Survival / Q000276:immunology*; D007136:Immunoglobulins / Q000008:administration & dosage*; D016381:Islets of Langerhans Transplantation; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology*
chemical_list: D060908:CTLA-4 Antigen; D007136:Immunoglobulins; C527086:Klrk1 protein, mouse; D055655:NK Cell Lectin-Like Receptor Subfamily K
keywords: Alloantigen; basic (laboratory) research/science; immunosuppression/immune modulation; islet transplantation; rejection; translational research/science