A new immunodeficient hyperglycaemic mouse model based on the Ins2 Akita mutation for analyses of human islet and beta stem and progenitor cell function

Abstract

Aims/hypothesis To develop and validate a new immunodeficient mouse strain that spontaneously develops a nonautoimmune hyperglycaemia to serve as a diabetic host for human islets and human beta stem and progenitor cells without the need for induction of hyperglycaemia by toxic chemicals with their associated side effects. Methods We generated and characterised a new strain of immunodeficient spontaneously hyperglycaemic mice, the NOD-Rag1 null Prf1 null Ins2 Akita strain and compared this strain with the NOD-scid Il2rγ null (also known as Il2rg) immunodeficient strain rendered hyperglycaemic by administration of a single dose of streptozotocin. Hyperglycaemic mice were transplanted with human islets ranging from 1,000 to 4,000 islet equivalents (IEQ) and were monitored for normalisation of blood glucose levels. Results NOD-Rag1 null Prf1 null Ins2 Akita mice developed spontaneous hyperglycaemia, similar to Ins2 Akita -harbouring strains of immunocompetent mice. Histological examination of islets in the host pancreas validated the spontaneous loss of beta cell mass in the absence of mononuclear cell infiltration. Human islets transplanted into spontaneously diabetic NOD-Rag1 null Prf1 null Ins2 Akita and chemically diabetic NOD-scid Il2rγ null mice resulted in a return to euglycaemia that occurred with transplantation of similar beta cell masses. Conclusions/interpretation The NOD-Rag1 null Prf1 null Ins2 Akita mouse is the first immunodeficient, spontaneously hyperglycaemic mouse strain described that is based on the Ins2 Akita mutation. This strain is suitable as hosts for human islet and human beta stem and progenitor cell transplantation in the absence of the need for pharmacological induction of diabetes. This strain of mice also has low levels of innate immunity and can be engrafted with a human immune system for the study of human islet allograft rejection.

Amyloid Formation in Human Islets Is Enhanced by Heparin and Inhibited by Heparinase

“…scid) mice (6,36,37). Human islets were cultured in 11 mM glucose for 1 week prior to transplantation in the presence or absence of a high concentration of heparin (410 IU/mL).…”

Advancing Animal Models of Human Type 1 Diabetes by Engraftment of Functional Human Tissues in Immunodeficient Mice

“…Chemically Induced Hyperglycemic NSG Mice NSG mice have been induced to become hyperglycemic by the injection of streptozotocin (STZ) (King et al 2008;Pearson et al 2008b). Transplantation of human or mouse islets, or dissociated mouse islet insulin-positive cells can restore normoglycemia.…”

“…This spontaneously arising mutation replaces a cysteine at position 96 with tyrosine, and disrupts a disulfide linkage required for proper folding of Akita -harboring strains of immunocompetent mice (Pearson et al 2008b). There was no mononuclear cell infiltration into the islets that had spontaneously lost b cells, and human islets transplanted into diabetic NOD-Rag1 null Prf1 null Ins2 Akita mice resulted in a return to euglycemia.…”

“…null Ins2 Akita mice (Pearson et al 2008b). Furthermore, human islets can also restore normoglycemia in diabetic NRG-Akita mice.…”

Immunological Considerations for Inducing Skin Graft Tolerance

“…Pearson et al (Pearson et al, 2008) described the NOD-Rag1null Prf1null Ins2Akita spontaneously hyperglycemic mouse model. This model has no autoimmune defect, but may be used to study type 1 diabetes in an environment that avoids any toxicity associated with chemically induced diabetes models.…”