Investigators under Denise Faustman, MD, PhD, director of the Immunobiology Laboratory at the Massachusetts General Hospital, are bringing hope to those suffering from type 1 diabetes. In a type 1 diabetes mouse model they were able to achieve differentiation of the spleen cells into insulin-producing pancreatic islet cells.
MGH press office explains the research that was just published in Science:
Type 1 diabetes develops when the body’s immune cells mistakenly attack the insulin-producing islet cells of the pancreas. As islet cells die, insulin production ceases, and blood sugar levels rise, damaging organs throughout the body. In their earlier study, Faustman’s team directly attacked this process by retraining the immune system not to attack islet cells. They first used a naturally occurring protein, TNF-alpha, to destroy the mistargeted cells. Then they injected the mice with donor spleen cells from nondiabetic mice. A protein complex on these cells plays a key role in teaching new immune cells to recognize the body’s own tissues, a process that goes awry in diabetes and other autoimmune disorders.
The researchers expected to follow that process, which eliminated the autoimmune basis of the animals’ diabetes, with transplants of donor islet cells. However, they were surprised to find that most of the mice did not subsequently need the transplant: Their bodies were producing normal islet cells that were secreting insulin.
“The unanswered question from that study was whether this was an example of rescuing a few remaining islet cells in the diabetic mice or of regeneration of the insulin-secreting islets from another source,” says Faustman. “We’ve found that islet regeneration was occurring and that cells were growing from both the recipient’s own cells and from the donor cells.” An associate professor of Medicine at Harvard Medical School, Faustman notes that it has been generally believed that most adult organs cannot regenerate and that adult stem cells or cellular precursors would not be powerful enough to reconstitute functioning insulin-secreting islets.
In order to determine whether or not the new islets had developed from the donated spleen cells, the researchers carried out the same treatment using spleen cells from healthy male donors to re-educate the immune cells of female diabetic mice. In those diabetic mice that achieved long-term normal glucose metabolism, the researchers found that all of the new functioning islets had significant numbers of cells with Y chromosomes, indicating they had come from the male donors. In another experiment, donor spleen cells were marked with a fluorescent green protein, and again donor cells were found throughout the newly developed islets.
A separate experiment, however, indicated that islets also could grow from remaining precursor cells in the diabetic mice and resume insulin secretion once the autoimmune process had been halted. Such regrowth from the animal’s own cells was slightly slower than regeneration from donor cells – taking about 120 days – but the eventual regeneration of islets was just as complete. The result suggests that, given time, regrowth of islets can occur in animals who have immune system re-education to eradicate their diabetes but do not receive the donor islet cell precursors.
The researchers then separated spleen cells into those with a surface molecule called CD45, which indicates the cell is destined to become an immune cell, and those without CD45. They injected labeled spleen cells with or without CD45 – or unseparated cells – into young mice in which autoimmunity had begun but full-blown diabetes had not yet developed. After the immune system re-education therapy, all of the mice maintained normal glucose control, while their untreated littermates soon became diabetic. However, close examination of pancreatic tissue from the treated mice revealed markers from the donor cells only in the islets of those who had received spleen cells without CD45.
“It’s the cells without CD45 that are the precursors for pancreatic islets. They have a distinct function that has not previously been identified for the spleen,” Faustman says.
Faustman also hopes to investigate whether her diabetes-related discoveries could be applied to other autoimmune diseases, such as lupus and Crohn’s disease – two disorders believed by many to be caused by a similar disruption of the same immune process her team originally identified in diabetes.