Immunology: A tolerant approach

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Despite a long record of failure, a few immunologists continue to pursue precisely targeted therapies for autoimmune diseases. Ever since Ed Wiley learned that he had type 1 diabetes in 1997, he has fretted over his meals, blood glucose levels and the daily programming of his insulin pump. Wiley, a statistician who lives outside Boulder, Colorado, and works on big data analytics, has learned to live in a state of hypervigilance. Finding the right dose of insulin turned out to be more art than science and, like many with the disease, his control began slipping away with time. By 2008, he says, “my insulin doses just basically didn’t work any more”. Unable to reliably anticipate what he needed, Wiley was having severe hypoglycaemic episodes and was at risk of diabetic seizures and long-term disability. On his endocrinologist’s advice, he enrolled in a clinical trial of a novel drug called BHT-3021. Although technically a vaccine, BHT-3021 is not designed to stimulate an immune response, but rather to shut it down, stopping the body’s errant attack against cells in the pancreas that produce insulin. The goal is to achieve immune tolerance. Drugs that broadly suppress immunity are the standard treatment for autoimmune disorders such as multiple sclerosis (MS), rheumatoid arthritis and lupus. But these drugs can lead to life-threatening infections, and do not address the cause of the disease. Tolerance therapies are different. They aim to target only the immune cells that react to a specific antigen, a substance — in Wiley’s case, the insulin precursor proinsulin — that might trigger a response. “Why shut down a major arm of the immune system, if we’re just trying to restore tolerance to one antigen?” asks immunologist Larry Steinman of StanfordUniversity in California, who developed BHT-3021. This strategy, known as antigen-specific tolerance, is simple in concept. But, so far, dozens of clinical trials have failed to achieve a categorical success. And there is a fine line between calming the immune system and stimulating it, so these efforts risk making a disease worse — as happened in an MS trial some 15 years ago.

BHT-3021 is one of a new wave of treatments conceived by five veterans of the field that promises to do better. Early-stage trials show encouraging results in people with MS and type 1 diabetes. “A number of these approaches really are going to work,” predicts David Wraith, an immunologist at the University of Bristol, UK, and one of the few persisting in pursuing the work. “The science has caught up.” The approaches are varied, but they all rely on the body’s natural ability to distinguish its own substances from those of foreign intruders. When bacteria or viruses invade, some are swallowed by specialized antigen-presenting cells, or APCs. These chop up the bacterial or viral antigens and present them to T cells, white blood cells that orchestrate the immune response. The T cells then proliferate and launch a coordinated attack. APCs also ensure that normal daily maintenance does not turn deadly. As the body’s own cells continuously die and are replenished, APCs mop up the debris and present those self-antigens to T cells along with an array of proteins that signal that these cellular remnants pose no danger. In autoimmunity, for unknown reasons, this protective mechanism goes awry. The new therapies are designed to override this dysfunction by deliberately sending the relevant antigen to tissues where the body is likely to see it as a non-threatening part of itself. Most of the therapies developed so far target MS, which occurs when the immune system attacks the myelin sheath that protects neurons in the brain and spinal cord. Immunologist Stephen Miller of NorthwesternUniversity in Chicago, Illinois, designed a therapy that he and neurologist Roland Martin, now at University Hospital Zurich in Switzerland, began testing in patients in 2009. During the treatment, the patients’ white blood cells are extracted, chemically linked to seven myelin antigens, then reinfused. The cells make their way to the spleen, where they die and release the antigen, which is picked up by APCs.

Read more: Nature

April 15, 2014  Original web page at Nature


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