Resistance of spontaneously diabetic Ins2(akita) mice to allograft tolerance induced by anti-CD154 therapy

Transplant Proc. Jul-Aug 2014;46(6):2007-9. doi: 10.1016/j.transproceed.2014.06.012.

Abstract

Background: Despite ongoing advances in the clinical islet transplant field, progressive decline in graft function continues to reduce the long-term success of islet transplantation for restoring euglycemia in type 1 diabetic recipients. To preserve graft function and avoid the use of chronic immunosuppressive drug therapy, a key goal is to induce donor-specific immune tolerance to islet transplants. Preclinical rodent studies of islet transplantation largely utilize models of diabetes either induced experimentally with beta cell toxins or spontaneously occurring in strains genetically prone to autoimmune diabetes. In this study, we sought to determine if chronic, severe hyperglycemia itself, independent of both beta cell toxins and host autoimmunity, influenced acute allograft rejection and/or the capacity to induce allograft tolerance.

Method: To this end, we studied the response to islet allografts in severely diabetic, non-autoimmune C57Bl/6 Ins2(akita) recipients.

Results: Results indicate that diabetic Ins2(akita) mice display higher levels of blood glucose, show more rapid acute islet allograft rejection, and are resistant to allograft prolongation induced with anti-CD154 therapy relative to wild-type littermates rendered diabetic with streptozotocin. As such, results suggest that severe hyperglycemia may be an independent risk factor impacting the capacity to induce tolerance to islet allografts. Thus, Ins2(akita) mice represent a stringent model for evaluating anti-rejection strategies in the setting of severe metabolic demand on islet transplants.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / therapeutic use*
  • Blood Glucose / metabolism
  • CD40 Ligand / immunology*
  • Diabetes Mellitus, Experimental / etiology
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / surgery*
  • Graft Survival / immunology
  • Immunologic Factors / therapeutic use*
  • Islets of Langerhans Transplantation*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Transplantation Tolerance*
  • Transplantation, Homologous

Substances

  • Antibodies, Monoclonal
  • Blood Glucose
  • Immunologic Factors
  • CD40 Ligand