Tryptophan metabolites play an important role in the immune system

Tryptophan is the source of Thanksgiving legend and grist for a "Seinfeld" episode, but it's not the chemical that you'd expect to find in Lawrence Steinman's lab.

A professor of neurology and neurological sciences and chair of the immunology program, Steinman, MD, and his lab generally focus on high-tech genetic therapies for diseases of the brain and nervous system. But his latest paper, to be published in the Nov. 4 issue of Science, breaks new ground on the effects of tryptophan - an amino acid found in turkey, among other foods, that is rumored to cause extreme post-Thanksgiving-feast sleepiness. It was featured in "Seinfeld" as a way for Jerry to knock out a woman by feeding her turkey so he could play with her classic toy collection.

The myth of tryptophan in turkey causing inordinate sleepiness has been debunked (tryptophan only works on the brain when ingested on an empty stomach). But the amino acid itself does play a vital role in sleep and in control of mood. And Steinman's findings add to the growing body of evidence indicating that tryptophan plays a pivotal role in the immune system.

In an animal model, Steinman's group has found that certain tryptophan metabolites - molecules formed as the body breaks down the amino acid - work as well as any other existing medicines to alleviate multiple sclerosis symptoms. In multiple sclerosis, the immune system launches an attack against the myelin sheath, the fatty cells that insulate neurons. The resulting variety of neurological disorders affects more than 2.5 million people worldwide.

Soothing the overactive immune system of autoimmune diseases such as multiple sclerosis requires something that can suppress the attack. In their studies, the team discovered that a drug chemically similar to metabolized tryptophan is suppressive to the immune system. This drug, marketed as tranilast, has been used abroad in clinical trials for other indications and appears safe.

"The bigger message here is that diet and immunity are inextricably linked," said Steinman. The intersection between diet and the immune system has not been well-studied, he said, "but now all of a sudden we have this really interesting science that ties tranilast up with tryptophan, underscoring the remarkable effect diet can have on immunity."

For all his current enthusiasm, Steinman was a reluctant entrant into the world of tryptophan research. When one of the lead authors, German postdoctoral researcher Michael Platten, MD, PhD, approached Steinman in 2002 with his idea to try tranilast in Steinman's models of multiple sclerosis, Steinman thought it was one of the worst project proposals he had ever heard. The drug wasn't invented at Stanford and was already being used for a range of maladies. Steinman prefers to create his own therapies.

But Platten had his own funding through the privately held Australian company Angiogen Pharmaceuticals, so Steinman was game to see where the idea could go. None of the Stanford researchers have any financial ties to the company. Michael Selley, MD, Angiogen Pharmaceuticals' CEO and founder, is listed as one of the paper's 13 co-authors.

Platten and Peggy Ho, PhD, a postdoctoral researcher in Steinman's lab, performed a rigorous series of experiments using mouse cells and a mouse model of multiple sclerosis called experimental autoimmune encephalomyelitis, or EAE. The team detailed the effect of four tryptophan metabolites as well as tranilast, a synthetic derivative of tryptophan.

The researchers found that all of the chemicals alleviated symptoms of mice with EAE. They also found that if they injected EAE mice with immune cells from other mice that had been protected with treatment, they could transfer the protective effect of the tryptophan metabolites. "That was a very powerful result," said Ho. "I had been skeptical of this project, but I was amazed when I saw that."

Transference of protection indicates that the treatment might trigger regulatory T cells, cells that suppress immune response rather than activate it. Steinman admitted that the only explanations of this phenomenon currently amount to "hand waving."

"One of the questions that is bound to come up with all this is, 'So, doctor, if I eat a lot of this or that, can I cure my autoimmune disease?'" said Steinman. "Even though many of the things we study in the lab, like tryptophan, modulate the immune system, are there practical things you can do in your diet to make a difference? My answer to that is 'I don't know.'"

Steinman speculated that given the proven safety record of tranilast, as well as its apparent ability to suppress autoimmune diseases, it might be a practical way to achieve the benefits of tryptophan breakdown products without the complications of manipulating tryptophan consumption.

http://med.stanford.edu/