June 16, 2010 --
On December 23rd, 1953 at the Peter Bent Brigham Hospital in Boston, a team of surgeons carefully removed a healthy kidney from a 23-year-old man named Ronald Herrick. Working quickly, they wrapped the donor organ in a cold, wet towel, placed it in a stainless steel dish, and carried it into a different operating room. There, Ronald’s identical twin Richard lay dying of chronic nephritis. His brother’s healthy kidney was his only chance at survival.
The transplant, led by Dr. Joseph Murray, was successful; Murray later won the Nobel Prize in Medicine, Ronald lived healthily with one kidney, and Richard went on to marry his recovery room nurse. But while we now take kidney transplants nearly for granted, at the time of this operation, the world’s first successful human-to-human kidney transplant, their success was far from guaranteed. Before attempting the transplant, the doctors had performed 17 genetic tests to ensure that the brothers were indeed identical twins, including giving them reciprocal skin grafts and having them fingerprinted at the local police station. Doctors had not yet discovered a way to prevent the immune system from rejecting a transplanted organ, so at the time, the only way to be sure Richard would tolerate his new kidney was to make certain it was an exact genetic match.
Today we have sophisticated anti-rejection medications, known as immunosuppressive drugs, that have vastly improved the outcome and safety for patients receiving kidney transplants from donors who are not their genetic twins. But despite their success, there are significant problems even with the most advanced immunosuppressive drugs. First, they’re imprecise, reducing the effectiveness of the entire immune system – not just the cells going after the transplant. What’s more, they are expensive, leave patients at risk of serious infections and certain types of cancers, and paradoxically, they can damage the very organs they are meant to protect. They also must be taken for life. And so, today, a different question tantalizes researchers: whether there is a way to induce tolerance to kidney transplants without immunosuppressive drugs, even in people whose new organs are not an exact genetic match.
It is widely known that kidney transplant recipients need continuous treatment with immunosuppressive drugs so that they don’t reject : stop taking them and eventually you’ll lose your kidney. But over the years, doctors have heard rumors and anecdotal reports of exceptional patients who have maintained perfectly healthy transplants, some for years, without any immunosuppression whatsoever. Researchers have longed to study these “naturally tolerant” people to find out what gives their immune system this superhuman ability. Many, in fact, believe these rare few may hold the keys to drug-free transplantation for everyone. But there’s one big problem: naturally tolerant patiens are exceedingly rare. How rare? In three years of searching, Emory University transplant surgeon Dr. Kenneth Newell found only 25 in the whole of United States. To date, these 25 people are the largest reported cohort of naturally tolerant patients ever gathered.
Finding these patients was Dr Newell’s first challenge as head of the Immune Tolerance Network’s Registry of Tolerant Kidney Transplant Recipients. His second was finding out what sets them apart from regular transplant recipients. Newell’s goal was to identify biological signs, called ‘biomarkers’ that might indicate – or even predict -- tolerance. If they could find the correct biomarkers, doctors would then have a test that could tell them whether a person have some natural ability for tolerance. What’s more, they might uncover secrets that would guide the development of drugs to artificially induce tolerance in a safer way.
Newell and his team of ITN researchers collected blood samples from the tolerant patients, as well as from other groups for comparison’s sake, including healthy people who had never received a transplant, and healthy transplant patients who were taking immunosuppressive drugs. He divided the samples into two testing groups; one that he’d use to identify any telltale differences, and another he could reserve as a blinded test set to confirm his results. Newell first analyzed the various types of white blood cells in each blood sample and then looked deeper into the cells to find out genes were activated.
The results, published in the Journal of Clinical Investigation, are tantalizing. Newell found that tolerant patients had white blood cell populations significantly different from their medicated peers, with an increased number of less mature and unactivated B cells. He also found three particular B cell genes, all involved in B cell development, that were expressed more in the tolerant patients. Most importantly, when the researchers applied this “B cell signature” to their blinded test set to see whether it alone could correctly separate out the tolerant samples from the immunosuppressed samples, it did so with great accuracy. Their “signature” of tolerance correctly classified every one of the tolerant samples, and was wrong about only 1 (of 6) of the immunosuppressed samples. To Newell and his colleagues, this was a strong indication that these biomarkers were indeed the ones they were looking for.
The first question the researchers asked themselves, of course, is whether the immunosuppressive drugs themselves were causing these differences in people’s immune systems. But that doesn’t appear to be the case: the biomarkers also appeared in a small percentage of transplant patients who were still on immunosuppressive drugs. What’s more, the fact that these biomarkers showed up in medicated patients suggests that the number of people with natural tolerance -- or at least the ability to tolerate their transplants with a lower level of immunosuppression -- might be higher than previously estimated.
But how high? In order to find out, ITN is developing a new trial that will evaluate these biomarkers in a group of 250 stable kidney transplant patients who are still on full regimens of immunosuppression. The patients will be evaluated three times over two years , first, to determine what fraction of kidney transplant patients may be capable of some level of natural tolerance and second, to see if the biomarkers’ presence remains steady over time. The study also could help pave the way for future studies that see if these biomarkers can be used to identify which kidney transplant recipients may be safely weaned from their immunosuppressive drugs.
Before that can happen, researchers want to find out what this signature of tolerance tells them about the biology of tolerance. According to Laurence Turka, co-senior author of the paper, the biggest unanswered question is whether these biomarkers are the cause of tolerance or merely an indicator of it.
The ITN hopes that future research will lead to the achievement of several ambitious goals: a better understanding of tolerance, the development of new, less toxic therapies to induce tolerance in people who can’t achieve it naturally, and the possibility of designing custom-tailored treatment regimens for each patient. “I’m very hopeful that in the end we’ll be able to use these markers to develop individualized medicine,” says Newell. “You may require more immunosuppression than me or less – the real goal is to get each person to the precise amount they need.”
