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Natural immune-control system may hold clue to treatment of autoimmune disease and tissue rejection, study finds


 

The immune system's ability to police itself may offer a new method of arresting the cells responsible for autoimmune diseases such as multiple sclerosis and for the rejection of transplanted organs and tissues, scientists at Dana-Farber Cancer Institute report in a study in the May issue of the journal Immunity.

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 study authors indicate. Although the research was done in mouse cells, it is likely to apply to humans because of 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," says senior author Harvey Cantor, MD, of 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 pose a complex challenge to scientists. Both problems result from an attack by immune system cells — which are trained to detect and destroy infected or diseased tissue — on parts of the body where it isn't wanted. 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.

Conventional therapies for these conditions can have serious drawbacks. Many of them rely on natural substances called antibodies, which wedge inside "receptors" on immune system T cells. The coupling blindfolds T cells to the presence of foreign or diseased tissue, blunting their ability to spark an immune attack.

Antibody-based treatments fall short for a variety of reasons: the antibodies often fail to fit securely inside T cells receptors, so the immune response is only slightly reduced; or the antibodies succeed in blocking the receptor, but that inadvertently causes the T cells to launch a more ferocious attack. In other cases, antibodies work too well, suppressing the entire immune system, rather than just a portion of it, leaving patients susceptible to dangerous infections.

To overcome these problems, researchers have tried to harness the body's natural system for quieting the immune response. One intriguing approach involves the immune system's "natural killer," or NK, cells. Scientists have long known 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.

Cantor and his colleagues theorized 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 faulty version of it, preventing them from binding to the NKG2A receptor. The result was that the T cells became vulnerable to attack from a set of NK cells. Using an antibody to block the connection between Qa-1–Qdm and NKG2A had the same result.

"Our findings suggest that it is possible to use antibodies to trigger the body's own mechanism for suppressing the immune response," Cantor remarks. "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 work was done with mouse cells, the Qa-1–Qdm ligand has the same shape and structure in human and mouse T cells, raising hopes that the approach will prove effective in humans as well, adds Cantor, who is also a professor of pathology at Harvard Medical School.

The research was supported by grants from the National Institutes of Health, the National Multiple Sclerosis Society, the Claudia Adams Barr Foundation, and a fellowship from Taiho Pharmaceuticals of Japan.

The lead author of the study is Linrong Lu, PhD, of Dana-Farber. Co-authors include Koichi Ikizawa, PhD, Dan Hu, PhD, Miriam Werneck, and Kai Wucherpfennig, MD, PhD, all of Dana-Farber.

Dana-Farber Cancer Institute (www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute.

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