Synergy between Two Drugs Proves Especially Beneficial for Population of Diabetic Mice

Type 1 diabetes is a complicated disease, and not every therapy works for everybody. That’s why researchers are looking to tailor, or in a sense “personalize,” treatments for different people with the disease. Now, longtime JDRF-funded scientists from the La Jolla Institute for Allergy and Immunology, in collaboration with life sciences technology company Entelos, have done exactly that. They are taking a therapy they started to develop five years ago and identifying a population of diabetic mice that best responds to it. The findings, if translated to humans, would accelerate clinical trials and help identify people who are most likely to benefit from the therapy.

The treatment is composed in part of an anti-CD3 drug, which is a drug that suppresses the immune system. This type of drug was first used to treat transplant rejection and now is being investigated for the treatment of autoimmune diseases such as type 1 diabetes. It has long been known that the drug, when given at low doses, benefits mice and humans, but its effects do not last long. Higher doses or repeated treatment may increase anti-CD3’s protective effects, but at the cost of compromising the immune system. Recently, a JDRF-funded project led by La Jolla Institute researcher Damien Bresson, Ph.D., showed in animal models that oral insulin, when combined with a low dose of anti-CD3, can significantly prolong the protection against the autoimmune attack associated with type 1 diabetes without drastic immune disturbances and unwanted side effects.

Now, Dr. Bresson and Matthias von Herrath, M.D., director of the Type 1 Diabetes Center at the La Jolla Institute, demonstrated that the oral insulin–anti-CD3 combination therapy, when administered early enough, may be most effective in mice whose immune systems specifically attack insulin-producing beta cells, one of the main targets in type 1 diabetes. “We previously showed that we need an antigen-specific therapy to boost the effects of a non-antigen specific therapy,” says Dr. von Herrath. “Here, we show which mice best respond to this therapy—those whose immune systems turn against insulin.”

Along with predicting which people will benefit most from the combination treatment, the team also describes the mechanism behind its ability to be effective. It works by boosting the number of regulatory T cells, a component of the immune system that tames the autoimmune attack on insulin-producing beta cells. Because clinicians can measure these regulatory cells during treatment, this finding also gives the researchers a possible way to test whether the therapy is working.

The team says that the findings may be a big step forward in helping to bring this therapy into the clinic. If the therapy works in people, researchers would be able to select participants who are most likely to respond to it, and then continue treatment only in those who are successfully responding to it. These tools will help cut the costs of clinical trials while increasing the benefit to patients.

“We really believe that this combination therapy is ready to be tested in humans,” says Dr. Bresson, citing the long history both drugs have in clinical trials, and their well-established safety profiles. “We can envision the use of this approach for treating people who have been recently diagnosed with type 1 diabetes, as well as patients who have received transplants, where a sustained control of the autoimmune attack is required.”