Since the first insulin injection in 1922, a long-term cure for type 1 (insulin-dependent) diabetes has been a number-one priority among researchers. It may soon be reality, thanks to a collaboration of investigators at the La Jolla Institute for Allergy and Immunology in San Diego, according to a study published April 20 in the Journal of Clinical Investigation. Dr. Matthias von Herrath says his team combined short-term therapies for type 1 diabetes and cured around half of the mice used in the study. In a type 1 diabetic, symptoms begin to appear when the body loses roughly 80 percent of its beta cells - the pancreatic tissue responsible for producing insulin and enabling the body to use glucose for energy. The culprit of the disease is a diabetic's own immune system, specifically T cells known as CD4+ and CD8+. Like a tag-team, the CD4+ T cells detect a threat and then instruct CD8+ T cells to launch an attack. For reasons still not fully understood, these cells can become aggressive toward beta cells. Curing type 1 diabetes, von Herrath says, requires blocking the activity of aggressive T cells with their counterparts: Regulatory T cells, or Tregs. "As long as they're around, they're endogenous peacekeeping machines," von Herrath says. Previous researchers, von Herrath says, used human proinsulin to stimulate pancreatic Treg production. In a specific way, these Tregs protect beta cells by suppressing aggressive T cells that attack pancreatic tissue.
"Tregs can somehow talk to the aggressive cells and say 'you have to stop destroying beta cells because they're good for the body,'" says Damien Bresson, another member of the research team. But simply boosting their numbers does not reverse type 1 diabetes in the long run. Two clinical studies published in 2005 show vaccination with anti-CD3 antibodies, which suppresses the immune system, is the most effective way to combat the disease. "The cool thing is that (anti-CD3) treatment … halts beta cell destruction not only in mice, but also in humans," von Herrath says. According to the studies, 10 days of anti-CD3 treatment slowed beta cell destruction in humans for 18 months, but not without side effects such as "fever, nausea, and muscle aches, much like you have the flu," von Herrath says. And reversal is not permanent. Experimenting with a more long-term treatment, von Herrath's team combined anti-CD3 with the vaccination and observed something exciting: Beta cells began to regenerate and permanently reverse type 1 diabetes in half of the mice - almost twice as much as using anti-CD3 alone. "Once we applied the therapy to diabetic mice, those that reversed stayed non-diabetic for the rest of their lives," von Herrath said. One possible explanation for the effectiveness of the combined therapy, von Herrath says, is that an auto-destructive immune system tips in favor of saving beta cells instead of destroying them. Anti-CD3 suppresses aggressive T cells, creating a "window of opportunity" for the vaccine to boost pancreatic protection and permit beta cell regeneration. Because some beta cells are still destroyed in the process, antigens are continuously released, Treg production is maintained, and protection continues for the remainder of a mouse's two-year life.
