Toward tolerating transplants | Philadelphia Inquirer | 01/28/2008

A Children's Hospital researcher is working to enable patients to accept new organs without taking potent drugs the rest of their lives.

Posted on Mon, Jan. 28, 2008
By Josh Goldstein
http://www.philly.com/inquirer/health_science/weekly/20080128_Toward_tolerating_transplants.html

Inquirer Staff Writer

Organ transplantation is one of the crowning achievements of modern medicine, but surgical success comes at a price.

Recipients must take powerful drugs - with not-infrequent serious side effects that include infections, kidney damage and cancer - for the rest of their lives to prevent rejection of the new organ. Even so, one-third of them will need another transplant within 20 years because their donated organs wear out.

So ever since the first successful transplants five decades ago, finding a way to get patients to accept their new organs without the need for immune suppression - known as graft tolerance - has been a key goal for medical researchers.

At Children's Hospital of Philadelphia, Australian-born pathologist Wayne Hancock is pursuing a solution that so far has had promising results, at least in mice.

"We can induce tolerance," he says - at least in transplanted laboratory mice.

Working on the most basic level of the immune system - the genes that control T cells, the body's main line of defense against alien invaders - Hancock and his team have succeeded in getting mice to accept the transplants as their own following a brief course of drugs that are already approved for other uses. After two weeks, they were drug-free.

"Immune suppression causes really all of our other problems," says Elizabeth Rand, medical director of Children's Hospital's liver transplant program. "Inducing graft tolerance is really the Holy Grail of organ transplantation."

Hancock's latest research, published two months ago in the journal Nature Medicine, has potential beyond transplantation.

It could lead to treatments for autoimmune disorders ranging from inflammatory bowel disease to multiple sclerosis, and perhaps even the asthma and diabetes that afflict millions.

That would be a big plus, but Hancock is most interested in helping the nearly 30,000 Americans who have transplants each year and currently require lifelong immune suppression.

Researchers all over the world are seeking a better approach. Just last week, three brief reports in the New England Journal of Medicine examined inducing tolerance in small numbers of transplant patients under special circumstances.

"Taking the immune system out of the equation would be a big improvement," Karl L. Womer, a physician-scientist at Johns Hopkins University School of Medicine whose research focuses on transplant immunology, says of Hancock's work. "There is definitely a long way to go."

Hancock knows it's one thing to succeed with mice, which lead relatively germ-free lives in the laboratory, and quite another with humans, who are exposed daily to myriad bacteria and viruses.

Still, his approach is promising enough to garner a five-year grant from the National Institutes of Health.

Hancock's goals are simple - to "contribute to the development of more effective and safer ways to . . . prevent transplant rejection with less toxicity and side effects," he writes in a grant proposal.

And he genuinely wants to do good. A nice side benefit is that the hunt for answers is intellectually stimulating and just plain exciting to the Aussie.

In the early 1990s, things seemed much more bleak. He had lost his U.S. visa and was forced to returned to Australia, where he was working in a pathology lab.

Then one Sunday morning in 1992, as Hancock lay awake in bed contemplating a dull future reading routine patient test results day after day after day, the phone rang. Harvard wanted him back in the States to search for solutions to the problem of immune suppression.

Sixteen years later, after a foray into industry with a biotech firm and now with his own lab at Children's Hospital, the 53-year-old pathologist thinks his team is closing in on a real, broadly applicable approach.

Hancock's research is focused on a subset of T cells known as regulatory T cells. Although they are an integral part of the immune system, the balancing act assigned to T-regs is to suppress it, thus preventing the body from attacking itself.

So, for example, tissue samples from mice with a form of inflammatory bowel disease - an autoimmune condition characterized by ulcers in the lining of the colon - reveal very few T-reg cells, and those that are present are not active. To treat these mice, the researchers injected a type of drug known as an HDAC inhibitor. The mice then produced more, and more effective, T-reg cells.

Likewise, mice that had heart transplants and were then treated with HDAC inhibitors developed increased numbers of T-regs. After two weeks of treatment, the mice had accepted the new organs and required no further immune suppression.

The drugs - histone deacetylase inhibitors - were developed for cancer treatment and approved by the Food and Drug Administration for clinical use.

Hancock's research shows that the HDAC inhibitors act on a key gene and the protein it produces to increase T-reg numbers and function. Now Hancock and his team have begun testing their approach on monkeys.

Hancock's findings suggest another possible use beyond treatment: Measuring the numbers and function of a patient's T-reg cells in blood or tissue samples might eventually be used to diagnose autoimmune problems and organ rejection.

So far, his work with regulatory T cells has gotten to the point that others in the field might call intriguing.

"It is an interesting idea and potentially practical approach that awaits confirmation," says Terry Strom, a professor of immunology at Harvard Medical School. "The approach merits serious review and critical follow-up experiments."

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Contact staff writer Josh Goldstein at 215-854-4733 or jgoldstein@phillynews.com.
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