Regeneration of the β cell in diabetic NOD mice. (A) In NOD mice, the infiltration of autoreactive T cells into the islets of Langerhans (resulting in insulitis) begins at around 4 weeks of age. At 20 to 23 weeks, approximately 85% of female mice are diabetic, i.e., their glycemia is greater than 300 mg/dl. Magnification, ×200. (B) When it is successfully transplanted with bone marrow from a non–diabetes-prone donor and hematopoietic chimerism is established, the NOD mouse no longer show signs of autoimmune activity. However, while there is no more evidence of insulitis in the endogenous pancreas, there is also no sign of insulin production (no red staining). Magnification, ×400. (C) Insulin-positive cells in the islets can be seen to be dividing (yellow arrows); i.e., they are insulin (blue) and BrdU (red) positive. Magnification, ×400. (D) Three to 4 months after bone marrow transplantation, new insulin-positive cells (shown in red) are present throughout the endogenous pancreas. Magnification, ×200. Thus, when the islets transplanted under the kidney capsule in order to maintain euglycemia while regeneration takes place are removed by nephrectomy, the mice remain nondiabetic. Figure reproduced with permission from Stem Cells (33).