Immune booster also works in reverse

A multitasking immune protein once pursued as a treatment to rev up the body’s defenses might work better at toning them down. The compound, called interleukin-2, can halt and even reverse aberrant immune reactions where standard treatment has failed, French and U.S. research teams report in the Dec. 1 New England Journal of Medicine.

Interleukin-2, or IL-2, is a signaling protein that has been approved for use against cancer and was also tried as an immune booster for fighting HIV, the AIDS virus. But despite some success against melanoma and kidney cancer, IL-2 has been a disappointment. It turns out that IL-2 does more than send immune fighters into battle. It also ratchets down these defenses by triggering production of T regulatory cells, or T-regs, which keep other immune troops in line. That quality could benefit patients with disorders in which the immune system attacks healthy tissues, such as lupus, multiple sclerosis or rheumatoid arthritis.

Both new studies take advantage of IL-2’s alter ego. Low-dose injections of the protein boosted T-reg levels, dampening immunity and improving symptoms in half of the U.S. patients, who had complications arising from bone marrow transplants, and in nearly all of the French patients, who had problems related to hepatitis C.

Although the small studies are “more like case reports,” the early findings could signal a major shift in IL-2 use, says Jeffrey Bluestone, an immunologist at the University of California, San Francisco who wasn’t involved in the studies. “It might be a tricky balancing act, but perhaps IL-2 at the right doses at the right times can promote T-regs preferentially” and quell immune mutiny.

The researchers in France identified 10 hepatitis C patients who had a reaction called vasculitis in which their immune systems unleash rogue antibodies that damage blood vessels. Giving the patients daily IL-2 injections on and off over 10 weeks improved symptoms in eight of the 10 patients. Levels of T-regs in these patients more than tripled during IL-2 treatment, but levels of the hepatitis C virus in the patients also fell, suggesting that the treatment didn’t shut off normal defenses, says study coauthor David Klatzmann, an immunologist at Pierre and Marie Curie University in Paris.

In the U.S. study, hematologist John Koreth of the Dana-Farber Cancer Institute in Boston and his colleagues monitored 23 people who had received a bone marrow transplant for leukemia or lymphoma. In these people, the donor cells were attacking their new host, a complication called graft-versus-host disease. Steroids or other medication had failed to control the condition.

IL-2 injections over eight weeks stabilized the graft-versus-host disease in 11 of the patients and relieved symptoms in the other 12, who showed fewer skin lesions, improved liver function and better mobility. Ten patients have continued on IL-2 for the long term, and some of them no longer need immune suppressant drugs, Koreth says.

Previous attempts to use T-regs directly as a treatment proved complicated since that required growing the cells in culture. Simply giving low doses of IL-2 lets the body do that work, says Thomas Malek, an immunologist at the University of Miami who wasn’t involved in the studies. The key, he says, will be careful dosing of IL-2 to ensure, with its multiple talents, that it doesn’t switch on the wrong immune cells.

Klatzmann’s team has now turned to using IL-2 against type 1 diabetes, while the Boston scientists are exploring the use of IL-2 earlier in the course of graft-versus-host disease.