Study points to unexpected treatment for type 1 diabetes

�With only a brief treatment, we have reversed an established autoimmune disease in a respected animal model,� says Denise Faustman, MD, PhD, of the Immunobiology Laboratory at MGH and principal investigator of the study. �Although the results are preliminary, this is an exciting finding for diabetes.�

Faustman�s treatment involves re-training the immune system in order to halt the disease that causes the destruction of islet cells, the insulin-secreting cells of the pancreas. The apparent permanent reversal of established disease allows the host to remake insulin from the pancreas by regrowth of islet cells that are no longer under attack.

Normally, the body�s immune cells attack toxins and foreign invaders, such as bacteria and viruses. In type 1 diabetes, though, the immune cells somehow receive a faulty signal, and their destructive efforts are instead directed toward the insulin-secreting islet cells. This results in a decrease of insulin � a molecule necessary for the conversion of glucose into fuel � and a subsequent increase in glucose. As glucose accumulates in the blood, it can damage organs, leading to conditions such as heart disease, kidney failure and blindness.

For the past five years, Faustman and her team have been closely examining the immune cells of diabetic mice and humans. They came across two key findings: the immune cells died when they were exposed to the naturally occurring drug, TNF-alpha, and many of the immune cells were unable to present self-peptides � a process crucial for preventing the development of autoimmune reactions.

Because of these two findings, Faustman and her team designed a two-pronged treatment strategy. First, they triggered the expression of TNF-alpha in the mice in an attempt to destroy the immune cells that had gone awry. This approach had never been used for the treatment of type 1 diabetes. On the contrary, TNF-alpha antagonists have been prescribed, an intervention that never permanently reverses or cures the disease. Antagonists of TNF-alpha are often used in the clinic as a general treatment for suppressing inflammation. �According to our findings, future efforts for diabetes treatment should look at using TNF agonists instead of antagonists,� says Faustman.

In the next step of the two-pronged approach, the researchers addressed the lack of self-peptide presentation. The diabetic mice were injected with donor cells that expressed the self-peptides. This treatment re-educated the newly emerging immune cells of the mouse, ensuring that they do not attack the islet cells.

Up to 75% of the treated mice had normal blood glucose levels that persisted beyond 100 days after the treatment was discontinued. Faustman and her group found no need to administer islet cell transplants or to intervene in a pre-diabetic state, the two major treatment approaches used for type 1 diabetic patients today. �With islet cell transplantation you need a tissue source, you need long term immunosuppression and the disease recurs,� says Faustman. She also says that trying to attack the disease before it actually develops is expensive, especially when it comes to pinpointing �potential� diabetics by looking for a genetic link. The only other current option for diabetic patients is to treat the complications, says Faustman. In essence, individuals monitor their glucose levels and inject themselves with insulin.

Faustman is working with David Nathan, MD, of the Diabetes Unit at MGH, to bring her new treatment approach to the clinic. Funding for the current study was provided by The Iacocca Foundation.

The 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 $300 million and major research centers in AIDS, the neurosciences, cardiovascular research, cancer, cutaneous biology, transplantation biology and photo-medicine. In 1994, the MGH joined with Brigham and Women�s Hospital 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.