Immune Cell Traitors Abet Gene Therapy

Scientists have coaxed the immune system of mice to let down its guard and allow a virus to deliver therapeutic genes. The method, reported in the November issue of Nature Biotechnology, could lead to safe and effective human gene therapies for cystic fibrosis, hemophilia, and a variety of other diseases.

Scientists already know how to use a weakened strain of a respiratory virus called adenovirus to transport healthy genes to cells. But immune warriors called cytotoxic T cells often attack the virus-infected cells. Unfortunately, disarming T cells can cripple the body's ability to battle viral infections and cancer. So immunologist John Mountz, virologist Huang-Ge Zhang and their colleagues at the University of Alabama, Birmingham, decided to help the body double cross only those T cells that kill adenovirus-infected cells in mice.

The team first enlisted a second type of immune cell, called an antigen-presenting cell (APC). Normally, APCs infected with adenovirus will alarm some cytotoxic T cells, which then multiply to battle the infection. To overcome that reaction, they gave the cultured APCs a lethal weapon--a protein called FasL. They found that those APCs home in on and kill the T cells gearing up to fight adenovirus. Mice pretreated with these engineered APCs expressed a foreign gene for 50 days after adenovirus infection, more than twice as long as in untreated mice. And although the immune system of the treated mice could no longer kill adenovirus-infected cells, it could still attack and kill cells infected with an unrelated virus.

Other experts say the method could help induce the immune system to tolerate other gene therapy agents beside adenovirus. "It provides the possibility of overcoming the immune barrier to gene therapy, says immunologist Youhai Chen of the University of Pennsylvania School of Medicine in Philadelphia. And the method may also help treat autoimmune diseases and block transplant rejection, says gene therapist Paul Robbins of the University of Pittsburgh School of Medicine: "It's a proof of principle that you can tolerize against specific antigens. That has far-reaching implications."

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