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For some time, Dr. Kevan Herold has wanted a longer honeymoon for his diabetes patients. The honeymoon period is when the destruction of insulin-producing cells slows for a few months in individuals with Type 1, or juvenile, diabetes after they are diagnosed. But now, Dr. Herold has obtained his wish. With just a two-week course of a new designer drug, Dr. Herold and colleagues have produced a year-long honeymoon, essentially stopping the killing of insulin-producing cells in newly diagnosed Type I diabetes patients.

"The therapy may become important in reducing the life-threatening complications of diabetes," says Dr. Herold, associate professor of clinical medicine in the Naomi Berrie Diabetes Center. The findings from the small phase I/II trial, which measured the safety and effectiveness of the new drug, appeared in the May 30 issue of the New England Journal of Medicine.

Type I diabetes is an autoimmune disease that typically begins in childhood. T cells attack the insulin-producing beta cells in the pancreas, and as the cells die, the body gradually loses the ability to produce insulin. Usually, the disease is diagnosed before all the beta cells disappear, but little can be done to slow the loss. Insulin production continues to fall for several months until all of the beta cells are gone.

The new drug, a monoclonal antibody to the CD3 receptor on T cells, prevents the destruction of beta cells by blocking the T cells' activation. Dr. Jeffrey Bluestone, director of Diabetes Center at the University of California, San Francisco and co-author of the study, humanized a mouse antibody to prevent rejection of the foreign molecule and mutated the antibody in selected locations to prevent the activation of an additional immune response that causes high fever and low blood pressure.

The researchers gave the drug to 12 patients whose diabetes had been diagnosed within the previous six weeks to determine if the antibody could preserve the patients' remaining insulin production. The investigators administered the drug intravenously every day for two weeks.

After one year, insulin production stayed level or increased in 9 out of the 12 patients who received the drug, but only stayed level in 2 out of 12 control patients. The treated patients also had better control over their blood glucose levels. The risk of diabetic complications—such as kidney failure, heart failure, and stroke—drops when the blood sugar level is low and stable.

Although the drug works by suppressing the immune system's attack on the beta cells, the unique therapy selectively targets only T cells that are poised to kill beta cells. Prior immunosuppressive therapy to treat diabetes also saved beta cells but the drugs inhibited all T cell activity, leaving patients open to serious infections and even cancer. Also, unlike the traditional immunosuppressives, the new drug is not needed continuously, another factor reducing possible side effects.

Dr. Herold and Dr. Bluestone believe the new therapy induces a state of tolerance in the immune system that lasts even after the drug disappears. In tolerance, the T cells that mistake the beta cells as foreign still exist, but are quiescent. "We think our drug has re-educated the immune system and has shut down the T cells that go after the beta cells, or shut down the regulatory cells that control the T cells, but we don't know exactly how," Dr. Herold says.

Insulin production begins to decline 18 months after getting the antibody. The researchers hope to lengthen insulin production by administering the drug three times, instead of once, in the next trial planned for 80 patients. The Immune Tolerance Network, an international group of researchers funded by the National Institute of Allergy and Infectious Diseases, the National Institute of Diabetes and Digestive and Kidney Diseases, and the Juvenile Diabetes Research Foundation, will conduct the trial.

"If future trials extend our results, the antibody will be really important in making people's lives easier," Dr. Herold says. "People who make some insulin are better off than people who are completely insulin-dependent. They have fewer episodes of too-high and too-low glucose levels and, consequently, less risk of developing complications."

The National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, the National Center for Research Resources, and the Juvenile Diabetes Research Fund supported the research.


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