IMMUNOLOGY AND IMMUNOGENETICS
Preventing Diabetes Before it Begins
The autoimmune attack that destroys insulin-sensitive cells in the pancreas usually begins years before type 1 diabetes develops. It remains unclear what triggers this attack, but once it begins, lymphocytes invade the pancreas and begin to destroy the insulin-producing beta cells. As the attack escalates, other immune-system cells invade the pancreas. Eventually almost all the beta cells succumb, and the pancreas is no longer able to produce sufficient amounts of insulin. As blood glucose rises, the body cannot metabolize it and type 1 diabetes develops.
Researchers in the Section on Immunology and Immunogenetics conduct studies in order to better understand this complex and multi-step autoimmune process to identify potential targets for intervention. Although some of these insights may guide the development of new therapies for type 1 diabetes, the ultimate goal is prevention.
Investigations in the section range from basic experimentation in the laboratory to clinical trials involving patients with diabetes.
Analyzing the Attack
Using the most advanced molecular and genetic techniques, researchers in the section are deciphering the long sequence of immunological and genetic events that culminate in pancreatic islet-cell invasion and beta-cell destruction. They are trying to decipher the genes that predispose certain people to type 1 diabetes and to answer the question: Why are some individuals not tolerant of the beta cells in their pancreas?
Investigators also have taken the lead in identifying how the various immune-system cells —B and T lymphocytes, macrophages and natural killer (NK) cells—mobilize against the beta cells. They are now exploring the dynamic interaction among beta cells, antigens and immune-system cells and how this interaction causes type 1 diabetes.
Many of these studies are conducted in animal models, such as the non-obese diabetic (NOD) mouse, which develops an autoimmune form of diabetes strikingly similar to type 1 diabetes in people. By using such animal models and genetic modifications to alter particular genes, researchers can simultaneously study gene activity, immune system events and the diabetes changes that result.
The specialty of the section is the rapid translation of discoveries in mouse models to tests in patients with diabetes. For example, there is great interest in the discovery that NK cells, which normally attack tumor or virus-infected cells, can also help destroy beta cells in the pancreas of diabetic mice. Now they are testing patients’ blood samples to see whether the same might be true in humans.
Early Diagnosis and Intervention
Another major focus of the section is identifying people at risk of developing type 1 diabetes as early as possible, and testing new therapies to prevent the disease from developing.
Investigators in the section have taken the lead in improving imaging technology to make it possible to peer into the pancreas—a difficult feat given its location deep in the abdomen—to aid in diagnosis and assess how well therapies are working. In collaboration with colleagues at Massachusetts General Hospital, Joslin investigators have developed a magnetic resonance imaging method to allow one to directly follow the autoimmune attack on the pancreas. Initially tested in animals, the technique is now being evaluated in a small group of humans, with initially promising results.
In collaboration with physicians at Joslin Clinic, investigators in the section also are directing clinical trials of various agents that might prevent type 1 diabetes in high-risk people, reverse the course of the disease, or ameliorate it if caught very early. Several such trials are under way, and others are planned. Joslin has been one of the leaders in large multi-center consortia for clinical trials in type 1 diabetes.
Section Investigators:
Christophe O. Benoist, M.D., Ph.D. and Diane J. Mathis, Ph.D.
Richard A. Jackson, M.D.
Tihamer Orban, M.D.
