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An article just published in the Journal of Clinical Investigation—by lead authors Drs. Noel Maclaren and Anjli Kukreja of the Department of Pediatrics at Weill Cornell Medical College—sets out the results of an investigation into the immune defects of some 60 persons with immune-mediated diabetes, the most common form of type 1 diabetes. The study delineates precisely what predisposes a person to this condition, and the latest, best measures for diagnosis, prediction, and therapy. Above all, the authors suggest a new strategy for combating the disease: stimulate rather than suppress the patient's immune system.

Immune-Mediated Diabetes: The Defect

In immune-mediated diabetes, the person has lost the cells in the pancreas that secrete insulin. This happens through autoimmune destruction: the person's own immune system attacks the islet cells of the pancreas. The cause is a still incompletely understood combination of genetic abnormalities, and probably, in most cases, environmental factors.

In all their subjects with immune-mediated diabetes—about half, newly diagnosed children and adults, and the rest, adults with long-standing disease—the authors found a deficiency in certain kinds of white blood cells—specifically, the lymphocytes known as natural killer T cells (or NK T cells) and CD4+/CD25+ T cells. Together, these are called T regulatory cells (Treg cells), because they regulate the immune system and protect the body from being attacked by its own defenses.

The deficiency is an absolute requirement for immune-mediated diabetes, but not everyone with the deficiency will develop the condition. On the other hand, a person with the deficiency may develop other autoimmune diseases, such as thyroiditis, Addison's disease, vitiligo, and multiple sclerosis.

Diagnosing and Predicting the Disease

Testing for this defect in NK T cells and CD4+/CD25+ T cells is useful in diagnosing the immune form of type 1 diabetes—and predicting whether a likely suspect (a patient's sibling or other family member, for instance) might develop immune-mediated diabetes in the future. First, the family member is tested for antibodies to his or her islet cells. In a small percentage of cases, that test will be positive, indicating that the person is progressing toward the disease—although it is not yet certain that diabetes will develop. Then the family member is tested for the T regulatory cells, and, while a person without the deficiency at this time might still evince the defect later, finding the defect at this point is strongly predictive that the disease will take hold and progress to diabetes.

A New Strategy for Treatment

Perhaps the most interesting aspect of the authors' findings is the implications for therapy. For several decades, doctors have tried to fight this autoimmune disease by suppressing the immune system, and the results have been disappointing. Patients have not been able to throw away their insulin needles, and, besides, they need their immune systems to fight colds, pneumonia, cancer, and a host of other diseases. But this study suggests a new, counterintuitive strategy: instead of suppressing the immune system, stimulating just the right part of it, the T regulatory cells. Since these cells are not totally absent from people with immune-mediated diabetes, they might be stimulated to function better.

To accomplish this stimulation of T regulatory cells, the authors point to a substance, alpha-galactosylceramide, which was originally found in deep-sea sponges off Japan, and which has turned out to be such an immunostimulant. Recent reports of its trials as a preventative in non-obese diabetic (NOD) mice have been "very encouraging," the authors say. They suggest human trials of synthetic forms of the substance in the near future.

A New Understanding of the Disease

Overall, the authors' focus on T regulatory cells leads to a new and more refined understanding of immune-mediated diabetes. In an interview, Dr. Maclaren illustrates this understanding by observing that natural killer T cells are believed to be stimulated by some environmental encounters—encounters with intestinal worms, for instance. Here in modern America, where such organisms as worms have largely been eliminated, it is possible that the rising incidence of immune-mediated diabetes has something to do with the efficient sterilization of our food. In India, by contrast, the environmental stimulants such as mycobacteria still are prevalent, and immune-mediated diabetes is less common. Moreover, when Indians migrate to America, their rates of the disease rise to the commonly found American levels. "The observation is a fact," says Dr. Maclaren. "Making the connection is, as yet, conjecture."

The other authors of the article are Giulia Costi, John Marker, Chenhui Zhang, Zhong Sun, Karen Lin-Su, Svetlana Ten, Maureen Sanz, Mark Exley, Brian Wilson, and Steven Porcelli. Drs. Costi, Marker, Zhang, Sun, Ten, and Sanz are also from Weill Cornell's Department of Pediatrics. Dr. Exley is from the Cancer Biology Program, Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston. Dr. Wilson is from Cancer Immunology and AIDS, Dana Farber Cancer Institute, Boston. Dr. Porcelli is from Albert Einstein College of Medicine, New York.

The research was supported by the National Institutes of Health, the American Diabetes Association, and the Eli Lilly Company. Dr. Kukreja, a pediatric postdoctoral fellow, received a fellowship grant from the Juvenile Diabetes Foundation.