Nov. 17, 2003 Cells from an unexpected source, the spleen, appear to develop into insulin-producing pancreatic islet cells in adult animals. This surprising finding from Massachusetts General Hospital (MGH) researchers, published in the Nov. 14 issue of Science, is a followup to the same team's 2001 report of a treatment that cures advanced type 1 diabetes in mice. In discovering the biological mechanism behind that accomplishment, the researchers also have opened a potential new approach to replacing diseased organs and tissues using adult precursor cells.
"We have found that it is possible to rapidly regrow islets from adult precursor cells, something that many thought could not be done," says Denise Faustman, MD, PhD, director of the MGH Immunobiology Laboratory and principal investigator of the study. "By accomplishing effective, robust and durable islet regeneration, this discovery opens up an entirely new approach to diabetes treatment."
David M. Nathan, MD, director of the MGH Diabetes Center, notes, "These exciting findings in a mouse model of Type 1 diabetes suggest that patients who are developing this disease could be rescued from further destruction of their insulin-producing cells. In addition, patients with fully established diabetes possibly could have their diabetes reversed." Nathan has developed a protocol to test this approach in patients, but additional grant support is needed before a clinical trial can begin. 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. Her work has largely been supported by grants from the Iacocca Foundation, founded by Lee Iacocca in 1984 to fund innovative approaches to a potential cure for diabetes. "The Iacocca Foundation has been willing to bet on projects that tackle the hard questions of autoimmunity," Faustman says. "We wouldn't be where we are today without their generous support."
"Dr. Faustman's research has significant implications not only to the future of diabetes treatment, but also to other autoimmune diseases," says Kathryn Hentz, president of the Iacocca Foundation. "It may someday be possible to apply her technique in reversing rheumatoid arthritis, multiple sclerosis and lupus."
The MGH research team has also received funding from the National Institute for Diabetes, Digestive and Kidney Diseases; the Cure Diabetes Now Foundation; and the American Autoimmune-Related Diseases Association Foundation. Co-authors of the Science paper are first author Shohta Kodama, MD, PhD; Willem Kuhtreiber, PhD; Satoshi Fujimura, PhD, and Elizabeth Dale, all of the MGH Immunobiology Laboratory.
The Iacocca Foundation has been leading the battle against diabetes for the past 20 years, becoming one of the world's major supporters of diabetes research. The foundation has granted more than $20 million to innovative and promising research designed to lead to a cure for diabetes and alleviate its complications. The Foundation was established by Lee Iacocca after his wife, Mary, died from complications of type 1 diabetes.
Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $350 million and major research centers in AIDS, cardiovascular research, cancer, cutaneous biology, medical imaging, neurodegenerative disorders, transplantation biology and photomedicine. In 1994, MGH and Brigham and Women's Hospital joined to form Partners HealthCare System, an integrated health care delivery system comprising the two academic medical centers, specialty and community hospitals, a network of physician groups, and nonacute and home health services.
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