Discovery Enables Autoimmune Disease Treatment Strategy

Scientists have found a new way to manipulate the immune system that may keep it from attacking the body’s own molecules in autoimmune diseases such as rheumatoid arthritis, type 1 diabetes, and multiple sclerosis.

The researchers, led by immunologist Mark Anderson, MD, PhD, a professor with the University of California, San Francisco (UCSF; USA) Diabetes Center, have discovered a unique type of immune cell called an extrathymic Aire-expressing cell (eTAC), which is found to suppress immune responses. Dr. Anderson’s research colleagues discovered that eTACs reside in lymph nodes and spleen in both humans and mice, and determined that they could be manipulated to block the destruction of the pancreas in a mouse model of diabetes. The study’s findings were published in the September 2013 issue of the journal Immunity.

Using green fluorescent protein (GFP) to illuminate a critical regulatory protein called AIRE (autoimmune regulator-1), Dr. Anderson’s research team searched out the rare eTACs and their role in a phenomenon known as peripheral tolerance, which helps prevent autoimmune disease throughout the body.

These immune cells are of a type known as dendritic cells, which comprise less than 3% of the cells in the immune system. ETAC cells account for a small fraction of all dendritic cells, according to the researchers. Dendritic cells already have been the basis of new cell therapies to treat cancer. These therapies, which include treatments assessed in UCSF clinical trials, have been used to induce dendritic cells to generate a complementary class of immune cells, called T cells. Treatment causes the T cells to target cancer cells, which, in spite of being abnormal, would not otherwise be exposed to forceful attack in the same way as foreign microbial intruders.

However, eTAC cells have the opposite effect. Instead of triggering T cells to fight, eTACs offset the overactive immune response in autoimmune diseases. Anderson's team took advantage of this property to demonstrate that eTACs could prevent autoimmune diabetes in mice.

By displaying “self” molecules to T cells that target them, and totally inactivating these T cells, eTACs help the immune system tolerate the molecules naturally present within us, according to Dr. Anderson. “The mouse model we are working with involves using T cells that normally attack the islet cells of the pancreas, specifically by recognizing a molecule called chromagranin A that is present on islet cells,” Dr. Anderson said. “But if the eTACs can get to the T cells first and display chromagranin A, they can prevent T cells from attacking the islets.”

Dr. Anderson is trying to exploit eTACs in a therapeutic way by determining how to grow them in large numbers outside the body. “We need to figure out how to grow a lot of these cells, to load them up with whatever molecule it is that we want to induce tolerance to, and then to load them back into a patient,” he said. “Such a strategy could help selectively shut down an unwanted immune response, such as the anti-islet immune response in type 1 diabetes.”

Dendritic cells work with T cells a bit like an investigator working with a bloodhound. Dendritic cells present not an article of clothing, but rather a specific molecule. If the molecule displayed by the dendritic cell matches the one the T cell was born to target, then that T cell would be triggered to increase its numbers and to attack cells or tissues where the molecule is present.

When the interaction is between eTACs and T cells, however, the targeted T cell instead is turned off forever, and never seeks its molecular target, Dr. Anderson noted, The first signal required for activation of a T cell is the display and recognition of the targeted molecule. But a second signal also is required, and eTACs are unable to deliver it, Dr. Anderson and colleagues discovered. They lack the molecular arms (molecules called B7-1 and B7-2) needed to communicate the activating message, which are present on other dendritic cells.

The eTACs arise in the bone marrow from adult stem cells that generate the entire blood system, including immune cells, according to Dr. Anderson. Compared to using pluripotent stem cells of nearly unlimited potential, it should be easier to determine how to guide the development of eTACs from bone marrow stem cells, he said.

Dr. Anderson’s search for an immune cell that in activates T cells began with the AIRE protein. He helped discover its function more than 10 years ago for specialized cells in the thymus. In the thymus, AIRE plays a major role in central tolerance, the occurrence whereby immune cells in thymus learn to tolerate the body’s naturally occurring molecules shortly after birth. Peripheral tolerance complements central tolerance, and its failure frequently is responsible for autoimmune diseases that arise well after birth.

Many UCSF faculty members are experts on immune tolerance and autoimmune disease. Another approach for exploiting the immune system to fight autoimmune disease, developed at UCSF, has already has led to a new therapy being assessed in a clinical trial for type 1 diabetes. The treatment is based on a type of T cell called the regulatory T cell, which plays a natural role in terminating immune responses when infection ends.

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