Successful Reversal of Streptozotocin-Induced Diabetes With Stable Allogeneic Islet Function in a Preclinical Model of Type 1 Diabetes

Abstract

The recent focus on islet transplantation as primary therapy for type 1 diabetes has heightened interest in the reversal of type 1 diabetes in preclinical models using minimal immunosuppression. Here, we demonstrated in a preclinical rhesus model a consistent reversal of all measured glycemic patterns of streptozotocin-induced type 1 diabetes. The model used single-donor islet transplantation with induction of operational tolerance. The term "operational tolerance" is used to indicate durable survival of single-donor major histocompatibility complex (MHC)-mismatched islet allografts without maintenance immunosuppressive therapy and without rejection or loss of functional islet mass or insulin secretory reserve. In this operational tolerance model, all immunosuppression was discontinued after day 14 posttransplant, and recipients recovered with excellent health. The operational tolerance induction protocol combined peritransplant anti-CD3 immunotoxin to deplete T-cells and 15-deoxyspergualin to arrest proinflammatory cytokine production and maturation of dendritic cells. T-cell deficiency was specific but temporary, in that T-celldependent responses in long-term survivors recovered to normal, and there was no evidence of increased susceptibility to infection. Anti-donor mixed lymphocyte reaction responses were positive in the long-term survivors, but all showed clear evidence of systemic T-helper 2 deviation, suggesting that an immunoregulatory rather than a deletional process underlies this operational tolerance model. This study provides the first evidence that operational tolerance can protect MHC nonhuman primate islets from rejection as well as loss of functional islet mass. Such an approach has potential to optimize individual recipient recovery from diabetes as well as permitting more widespread islet transplantation with the limited supply of donor islets.

Changes in Cyclooxygenase-2 Immunoreactivity in the Hippocampus in a Model of Streptozotocin-Induced Type 1 Diabetic Rats

“…Its toxicity is induced by DNA alkylating activity of its methylnitrosourea moiety, poly-ADP-ribose polymerase overstimulation, and cellular energy depletion [20]. In many studies including ours, STZ-induced animal models are used for studying the effects of type 1 diabetes mellitus [5,18,32].…”

Achieving Donor-Specific Hyporesponsiveness Is Associated with FOXP3+ Regulatory T Cell Recruitment in Human Renal Allograft Infiltrates

“…A better understanding of basic tolerogenic mechanisms (clonal exhaustion, deletion, and immune ignorance) as well as the capital role that T cells play during transplant rejection has resulted in different strategies trying to induce tolerance (1)(2)(3)(4)(5)(6); namely, T cell costimulation blockade, mixed chimerism induction, T cell depletion, and tolerance mediated by regulatory T cells (Tregs). 3 It is to note that some of these approaches have been already successfully proven in murine and in nonhuman primate models (7)(8)(9)(10)(11)(12). In the clinical setting, tolerance or "prope" tolerance has been defined as evidence of donor-specific un/hyporesponsiveness with recovered third party response in functional in vitro assays, lack of circulating donor-specific alloantibodies and absence of destructive lymphocyte infiltration in allograft biopsies in patients without or with minimal amount of immunosuppression.…”

Characterizing the induction of diabetes in juvenile cynomolgus monkeys with different doses of streptozotocin

“…Shibata et al tested three different doses of STZ in adult rhesus monkeys (2.57.5 years old), and found that 125 mg kg 1 of STZ could reliably induce diabetes without any risk, whereas 100 mg kg 1 of STZ failed to induce IDDM and two of the seven animals died within 7 h following an administration of 150 mg kg 1 of STZ [25]. In another study, Thomas et al found that all juvenile (23 years old, 3.13.8 kg) male rhesus macaques given 140 mg kg 1 of STZ developed type 1 diabetes, and this dose was not fatal [26]. These diabetic animals were maintained for >1 year, and no reversal of type 1 diabetes was observed [26].…”

“…However, the optimal dosage for IDDM induction in juvenile (23 years old) cynomolgus monkeys is still unclear. Additionally, other studies have also suggested that the genus and age of monkeys have an important effect on their sensitivity to STZ [25,26]. Therefore, in the present study, we characterized the induction of stable IDDM in juvenile cynomolgus monkeys (23 years old) using three different doses of STZ, in hopes of finding an optimal dose that produces minimal hepatic and renal toxicity.…”