Immunomodulators for Treatment of Type 1 Diabetes: An Overview

The following is an excerpt from Sara DeWeerdt’s wonderful article in Nature:

In the 1980s, studies demonstrated that suppressing the immune system of people recently diagnosed with T1D reduced their insulin dependence and provided persuasive evidence that T1D is an autoimmune disease. “Back then it wasn’t so clear,” says immunologist Jeffrey Bluestone of the University of California, San Francisco.

The early immunomodulators, such as cyclosporine and antithymocyte globulin, were blunt instruments, targeting not just the immune cells responsible for killing the beta cells, but other parts of the immune system as well. The drugs were too toxic for patients to take for extended periods, and any protective effect failed to persist after treatment. But even this limited effectiveness was enough to spur researchers to look for more specific immune modulators that would affect the precise mechanisms of beta-cell destruction in diabetes.

Much attention has focused on T cells, thought to be behind the targeted killing of beta cells in T1D. Antibodies against CD3, a receptor found on T cells, can prevent or even permanently reverse diabetes in non-obese diabetic (NOD) mice and other mouse models of T1D. “What was exciting in the mouse model was that we gave short-term dosing and we got long-term effects,” says Bluestone. He and other researchers hope that anti-CD3 might attenuate the immune system rather than switch it off with anti-rejection drugs.

Two different anti-CD3 antibody drugs, teplizumab and otelixizumab, have been tested in humans. Studies in Europe and the United States showed that a short course of treatment — two weeks or less — in people recently diagnosed with diabetes can improve beta-cell function for as long as five years.

In contrast to the mouse results, the effect in humans is temporary; eventually, beta-cell depletion begins again and the disease progresses. A bigger setback came in 2011, with the results of two large, phase III clinical trials of these agents on recently diagnosed patients. Although the design and endpoints of the studies were slightly different, both showed that the anti-CD3 approach did not improve on standard insulin therapy after one year¹.

That’s not an unfamiliar result. Indeed, Bluestone says, showing improvement over standard therapy is “really tough in the first year after diagnosis”. That’s because insulin formulations and delivery systems are now so good that most patients can easily keep their diabetes well controlled at first. Comparing any immunosuppression strategies to insulin treatment has been the undoing of a number of other drug treatments, he says.

For the full article in Nature, click here.  The article continues to disucss GAD trials, other antigens, such as insulin and its precursor, proinsulin, which might form the basis of other immune-modulating therapies, researchers studying the immune-modulatory effect of vitamin D, and more.