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Published On August 18, 2016

CLINICAL RESEARCH

A Tradeoff for T Cells

Researchers are looking into a simple, promising way to boost the immune system. But the price is steep.

The thymus is a pinkish-gray organ that sits just below the sternum. It functions as a school for your immune system’s T cells, creating them from blood stem cells, then educating them to seek and destroy infections such as viruses, bacteria and fungi as well as cancer cells. But the thymus naturally shrinks throughout life, and that largely corresponds with the body’s declining ability to fight off pathogens.

Researchers have been trying to find a way to stall or even reverse the thymus’s shrinking. Richard Boyd, an immunologist at Monash University in Melbourne, Australia, has focused on puberty, a time when the organ undergoes a dramatic reduction in size. Because testosterone, estrogen and other sex hormones ramp up during adolescence, Boyd wondered if these same hormones might somehow prompt the thymus to “involute”—to shrivel.

To test the idea, he castrated adult male mice by surgically removing their testes, halting production of testosterone. Sure enough, within four weeks, the animals’ thymi grew nearly as large and capable as those in younger animals. “It was a lightbulb moment,” Boyd says.

A bigger thymus might benefit a wide range of patients who suffer from immune deficiencies. The elderly have a harder time fighting off infections because their immune systems have run down, as have those of AIDS patients, whose T cells are depleted by the human immunodeficiency virus. Cancer patients see their immune systems take a hit from chemotherapy and radiation. But the drastic approach that Boyd took with mice could clearly not be repeated in humans.

Drugs do exist, however, that block sex hormones. Boyd treated male mice with a medication normally used to treat and prevent hormone-sensitive malignancies of the breast and prostate, called luteinizing hormone-releasing hormone agonists. Their thymi soon become as plump and youthful as those in castrated mice. Boyd then looked at elderly men with prostate cancer before and after they took the same hormone-blocking drugs. Their thymic output, as measured by circulating T cells, shot up as their sex hormones declined.

Blocking sex hormones to strengthen the immune system comes at a cost. For women, the loss of estrogen induces menopause. For men, losing testosterone can translate to fatigue, a loss of muscle mass, decreased sex drive and other problems. Both sexes may see a decrease in bone density. But Boyd says that hormone-blocking drugs would likely be used only briefly. And in some conditions, as in treating breast and prostate cancer, the benefit might be worth the price.

That could include some of the 20,000 people who receive bone marrow and peripheral blood stem cell transplants in the United States each year, often for cancers of the blood such as leukemia or lymphoma. Before the transplant, patients undergo chemotherapy and sometimes radiation to remove malignant cells. That stresses the thymus and suppresses immune defenses. After the procedure, these patients are essentially immunologically naked.

 “They live like AIDS patients,” says Marcel van den Brink, a transplant expert who researches thymic rejuvenation at Memorial Sloan Kettering Cancer Center in New York City. After bone marrow transplant surgery, patients are sequestered in their homes, eating carefully and avoiding contact with anyone who’s sick. Yet even with these precautions, many of these patients die of infections. Their immune systems regrow slowly and T cells—the cells that originate in the thymus—are the very last part of that system to recover. “If you can come up with strategies to boost thymic function, the payoff would be huge,” he says.

Blocking sex hormones has shown promise for these patients. In one 2008 study, van den Brink, Boyd and their collaborators showed that bone marrow transplant recipients taking the hormone-blocking drugs saw their immune systems recover more quickly. A year later, there were better survival rates for a subgroup of those patients who both took hormone-blocking drugs and received their transplants from healthy zones of their own bodies. Follow-up studies are ongoing at the National Cancer Institute and Memorial Sloan Kettering.

And there may be better ways to stimulate the thymus than with chemical castration. Van den Brink is studying the possibilities of thymic rejuvenation with an immune system signaling protein called interleukin-7. He’s shown that IL7 given to bone marrow transplant patients accelerated recovery of their T cells. Patients taking the treatment were also no more likely to develop graft-versus-host disease, a complication in which the cells from the newly transplanted marrow turn against the transplant recipient.

As a whole, the trials show the promise of thymic rejuvenation, with the hope that the body can be coaxed back into being its own best defense. “The thymus is never dead,” says van den Brink. “Yes, it involutes. But it can rebound.”