[show abstract][hide abstract] ABSTRACT: Insulin-dependent diabetes mellitus (IDDM) is the second most prevalent chronic illness of children. Investigation of the treatment of IDDM is hindered by the lack of a reproducible and easily maintained non-human primate model of this disorder.
We induced IDDM in 11 juvenile cynomolgus monkeys after a single (150 mg/kg) intravenous injection of streptozotocin (STZ). All diabetic monkeys were treated with insulin twice daily, based on a sliding scale. Subcutaneous vascular access ports were surgically placed in each monkey to facilitate serial blood sampling and drug administration. Allogeneic pancreatic islet cells from unrelated donors were subsequently transplanted into the mesenteric circulation of all STZ-treated monkeys.
Mild, transient nausea and vomiting occurred in all animals after STZ injection; however, no additional signs of toxicity occurred. Within 36 hr, all monkeys required twice daily administration of exogenous insulin to maintain a non-ketotic state. Serum C-peptide levels decreased from >1.2 ng/ml before STZ, to between 0.0 and 0.9 ng/ml after STZ, confirming islet cell destruction. Animals were maintained in an insulin-dependent state for up to 147 days without any observable clinical complications. Subcutaneous vascular access port patency was maintained up to 136 days with a single incidence of local infection. Islet cell transplantation resulted in normoglycemia within 24 hr. Serum C-peptide levels increased (range: 2-8 ng/ml) for 6 - 8 days in immune competent animals, and for 39-98 days after transplant in immunosuppressed monkeys.
IDDM can be consistently induced and safely treated in juvenile cynomolgus monkeys. Chronic vascular access can be maintained with minimal supervision and complications. This model is appropriate for studies investigating potential treatments for IDDM including islet cell transplantation.
[show abstract][hide abstract] ABSTRACT: Ag-specific T cell activation requires a CD28-mediated costimulatory interaction. This observation has suggested novel approaches to suppress donor-specific immunity, including the use of soluble CD28 antagonists, such as CTLA4Ig, which suppresses transplant rejection in small animal models. In this study, CTLA4Ig therapy was examined in a non-human primate model of allogeneic pancreatic islet transplantation. Two of five CTLA4Ig-treated monkeys showed prolonged graft survival, which correlated with donor-specific hyporesponsiveness in vitro. Humoral responses to the transplanted tissue were suppressed in all treated animals. These results suggest that CTLA4Ig is effective in suppressing both humoral and cellular immune responses in a non-human primate model of allogeneic transplantation.
The Journal of Immunology 12/1997; 159(11):5187-91. · 5.52 Impact Factor