June 30, 2009

Common Diabetes Drug Boosts Immune Memory

Illustration of an immune attack

In a new mouse study, researchers were able to boost the immune system's memory by using the anti-diabetic drug metformin. The unexpected finding could transform strategies for vaccine development.

The immune system can respond to a limitless repertoire of molecules, allowing it to adapt to virtually any pathogen that enters the body. It mounts a multi-pronged attack, producing a variety of different kinds of T cells, as well as B cells, which make and release antibodies.

The immune system also develops a memory of every pathogen encountered, so if you are exposed to the pathogen again, the system can quickly mount a strong response. Vaccines work by causing the immune system to "remember" specific molecules, or antigens, that are part of a bacterial cell, a virus, a fungus or even a cancer cell. The immune system's memory comes from T cells and B cells that have become specialized as memory cells. However, scientists haven't had a good understanding of how the system creates these cells.

A team of researchers led by Dr. Erika Pearce and Dr. Yongwon Choi at the University of Pennsylvania School of Medicine was studying the development of CD8 T cells, also known as killer T cells. These cells destroy cells infected with viruses or other pathogens, as well as damaged or abnormal cells. The researchers had previously created mice whose T cells lacked a protein called TRAF6 and found that it helps regulate immune responses. In the new study, the researchers tested how these mice responded to infection with bacteria. The study, funded by NIH's National Cancer Institute (NCI) and National Institute of Allergy and Infectious Diseases (NIAID), appeared in the online edition of the journal Nature on June 3, 2009.

Although the TRAF6-deficient mice mounted a powerful initial immune response to infection, the researchers found that the immune system failed to respond strongly to re-infection. Further experiments showed that the mice weren't producing T memory cells.

When the researchers compared the genes expressed by the TRAF6-deficient CD8 T cells with those expressed by normal cells, they discovered differences in several metabolic pathways, including fatty acid metabolism. Metabolizing, or breaking down, fatty acids for energy is an important survival pathway in cells undergoing metabolic stress.

Additional experiments showed that, while TRAF6-deficient cells proliferated normally in response to a growth factor, their response after growth factor withdrawal, which induces metabolic stress, didn't include the normal increase in fatty acid metabolism. The researchers reasoned that TRAF6-deficient cells may fail to survive as memory cells because they can't activate fatty acid metabolism after the peak of an immune response.

The anti-diabetic drug metformin is known to promote fatty acid metabolism, so the researchers tested it on the TRAF6-deficient cells and found that the drug restored fatty acid breakdown. Giving mice with TRAF6-deficient T cells either metformin or rapamycin, another drug that enhances fatty acid metabolism, restored memory T cell development after infection.

Metformin also increased the generation of memory cells in normal mice. Given with an experimental anti-cancer vaccine, the researchers found, it dramatically improved the efficacy of the vaccine.

The results show that manipulating energy metabolism during an immune response can promote memory cell generation and immunity. “These findings were unanticipated, but are potentially extremely important and could reshape strategies for both therapeutic and prophylactic [prevention] vaccines,” Choi says.

—by Harrison Wein, Ph.D.

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