Natural Immune-Regulation System May Inhibit Autoimmune Disease Cells that Lead to Tissue Rejection

The immune system's ability to regulate itself may offer a new way to suppress the cells responsible for autoimmune diseases such as multiple sclerosis and for the rejection of transplanted organs and tissues.

Scientists from Dana-Farber Cancer Institute (Boston, MA, USA) reported on their study in the May 2007 issue of the journal Immunity, available online. Because the technique utilizes the body's own mechanism for controlling the immune system, it may prove more effective and less prone to side effects than current therapies, which take a less direct approach, the researchers indicated. Although the study was conducted in mouse cells, it is likely the same mechanism will work in to humans because of the strong similarities between mouse and human immune cells.

"We found that when we block a key interaction between two types of immune system cells, one of those types--which is often associated with autoimmune disease and tissue rejection--is attacked and dies,” remarked senior author Harvey Cantor, M.D., from Dana-Farber. "The fact that this approach uses the body's natural system for regulating the immune response encourages us that it can be the basis of an effective therapy for a variety of immunological conditions.”

Autoimmune disease and tissue rejection present a complicated challenge to scientists. Both problems result from an attack by immune system cells--which evolved to detect and destroy infected or diseased tissue--in areas of the body where it is not needed. In the case of rejection, they recognize transplanted tissue as foreign and mount an assault on it. In autoimmune diseases, they attack the body's own tissue as through it were foreign.

Traditional therapies for these disorders can have severe drawbacks. Many of them rely on natural substances called antibodies, which lodge inside "receptors” on immune system T cells. The coupling blindfolds T cells to the presence of foreign or diseased tissue, suppressing their ability to initiate an immune attack.

Antibody-based treatments do not succeed for a variety of reasons: The antibodies frequently fail to fit securely inside T cells receptors, so the immune response is only slightly decreased; or the antibodies succeed in blocking the receptor, but that inadvertently causes the T cells to initiate a more ferocious attack. In other cases, antibodies work too well, suppressing the entire immune system, instead of only a portion of it, leaving patients susceptible to dangerous infections.

To overcome these hurdles, researchers have tried to harness the body's natural system for suppressing the immune response. One intriguing approach involves the immune system's "natural killer” (NK) cells. Scientists have known for a long time that some NK cells can kill a class of T cells--known as CD4 T cells--that have been activated to fight infection, but that NK cells are often restrained from doing so.

Dr. Cantor and his colleagues hypothesized that when a tiny hook, or ligand, called Qa-1-Qdm on activated CD4 T cells latches onto the NKG2A receptor on NK cells, the T cells are protected from destruction. To test this, they produced activated T cells that either lacked the Qa-1-Qdm receptor or had a defective version of it, preventing them from binding to the NKG2A receptor. The result was that the T cells became susceptible to attack from a set of NK cells. Utilizing an antibody to block the connection between Qa-1-Qdm and NKG2A had the same outcome.

"Our findings suggest that it is possible to use antibodies to trigger the body's own mechanism for suppressing the immune response,” Dr. Cantor remarked. "The results serve as a proof of principle that this approach can be applied to the treatment of conditions characterized by an excessive or unwanted immune response.”

While the study was performed with mouse cells, the Qa-1-Qdm ligand has the same shape and structure in human and mouse T cells, raising hopes that the application will be effective in humans as well, added Dr. Cantor, who is also a professor of pathology at Harvard Medical School (Cambridge, MA, USA).


Related Links:
Dana-Farber Cancer Institute