A Model for Human Islet Transplantation to Immunodeficient Streptozotocin-Induced Diabetic Mice

Abstract

Streptozotocin (STZ) is a cytotoxic glucose analogue that causes beta cell death and is widely used to induce experimental diabetes in rodents. The sensitivity of beta cells to STZ is species-specific and human beta cells are resistant to STZ. In experimental islet transplantation to rodents, STZ-diabetes must be induced before transplantation to avoid destruction of grafted islets by STZ. In human islet transplantation, injection of STZ before transplantation is inconvenient and costly, since human islet availability depends on organ donation and frail STZ-diabetic mice must be kept for unpredictable lapses of time until a human islet preparation is available. Based on the high resistance of human beta cells to STZ, we have tested a new model for STZ-diabetes induction in which STZ is injected after human islet transplantation. Human and mouse islets were transplanted under the kidney capsule of athymic nude mice, and 10–14 days after transplantation mice were intraperitoneally injected with five consecutive daily doses of STZ or vehicle. Beta-cell death increased and beta-cell mass was reduced in mouse islet grafts after STZ injection. In contrast, in human islet grafts beta cell death and mass did not change after STZ injection. Mice transplanted with rodent islets developed hyperglycemia after STZ-injection. Mice transplanted with human islets remained normoglycemic and developed hyperglycemia when the graft was harvested. STZ had no detectable toxic effects on beta cell death, mass and function of human transplanted islets. We provide a new, more convenient and cost-saving model for human islet transplantation to STZ-diabetic recipients in which STZ is injected after islet transplantation.

Donor-Specific Regulatory T Cell-Mediated Immune Tolerance in an Intrahepatic Murine Allogeneic Islet Transplantation Model with Short-Term Anti-CD154 mAb Single Treatment

“…One hundred twenty milligrams per kilogram of streptozotocin (STZ; Sigma-Aldrich, St. Louis, MO, USA) was intraperitoneally injected twice (one time a day) and only the mice with more than 16.8 mmol/l (=302.67 mg/dl) for three consecutive days were considered to have diabetic status 37 , 38 . After diabetic induction, mice were caged for the next 5 to 6 d prior to islet transplantation to excrete the remaining STZ from the body.…”

<p>Multifunctional Islet Transplantation Hydrogel Encapsulating A20 High-Expressing Islets</p>

“…This hypothetical model might be injected into several suitable sites in vivo, such as the beneath of kidney capsule, the peritoneal cavity, and a subcutaneous site on the back. 48,50 In the model, the hydrogel will be injected into body before gelation, then capillaries will creep into the hydrogel. With the release of immunosuppressants embedded in the model, the local immune isolation will be established.…”

Cholecystokinin Suppresses β-Cell Apoptosis, Including in Human Islets in a Transplant Model

“…A modified version of human islet transplantation described by Montanya et al . was used for the study 54 . A single high dose (200 mg/Kg) of streptozotocin (Sigma, #S0130) was administered via intraperitoneal injection two days before transplant to induce hyperglycemia.…”