Joining Forces to Improve Transplant Medicine

Posted in GUMC Stories

Surgeon Thomas Fishbein, MD, is on the cusp of solving a significant problem that he and all other transplant doctors face — the failure of transplanted abdominal organs. As executive director of the MedStar Georgetown Transplant Institute (MGTI), one of the nation’s leaders in intestinal transplants, he knows his opportunity is tremendous.

With a vision of one day preventing organ failures, Fishbein and Michael Zasloff, MD, PhD, director of surgical immunology and scientific director at MGTI, are enlisting an army of scientists at Georgetown University Medical Center to create the Center for Translational Transplant Medicine. The center is designed to expedite basic and translational research to benefit transplant patients. It brings to bear the expertise of a wide variety of laboratory scientists — immunologists, cell biologists, biostatisticians and a host of others who, in partnership with physicians who care for transplant patients, can collaborate seamlessly on ways to improve transplant outcomes.

While Fishbein and Zasloff expect to rapidly increase the number of clinical trials testing new therapies available to patients — already, about 20 are ongoing — they also plan to tackle what they call the “Holy Grail” of transplant medicine. “We need to suppress the ability of a patient’s immune system to reject a transplanted organ, but not suppress the body’s critical need to fight bacteria and other pathogens,” says Fishbein.

Zasloff explains that it is the drugs that patients must take to suppress the immune system from rejecting their “new” bowel that, ironically, leads to its demise.

As Fishbein says, “The gut has to deal with the bacteria that is crucial for its digestive function, and transplanted organs come with a lot of bacteria from the donor. The organ can fail because anti-rejection drugs suppress all immune function in the body, meaning that there is no natural way to keep the necessary level of bacteria in check,” he explains. “This problem happens with any transplanted organ that is exposed to environmental bacteria — the bowel, skin and lungs — and it happens most often to bowels. It doesn’t happen to transplanted hearts, because they are not exposed to the outside world and therefore, there is little bacteria in a heart to control.”

This analysis sounds like an explanation from a medical textbook — but actually, it is new knowledge. Fishbein and Zasloff have been on the cutting edge of understanding what scientists have only recently come to appreciate — that there are two different immune systems, each with its own army of cells and biological mechanisms that co-exist within the human body. What that means is the anti-rejection drugs suppress the adaptive immune system (which fights foreign tissue) as well as the innate immune system (which fends off pathogens).

Given this new information, Fishbein and Zasloff say it might be possible to design drugs that turn off or exquisitely modulate the adaptive immune system, and leave the all-powerful and protective innate immune system intact. Zasloff has spent much of his career studying the innate immune system in many life forms. He has found, for example, that a peptide isolated from a fungus that grows in northern European pine forests offers the same antibiotic power as penicillin, and that a compound isolated from sharks shows potential as a broad-spectrum human antiviral agent.

It will take a marriage of clinicians and scientists, such as the union that is occurring in the new center, to solve this immunity modulation problem, says Fishbein. “We have to integrate clinical programs and very sophisticated immunologic studies that can’t be done by either program alone,” he says. “When clinicians encounter problems in transplantation, we have to be able to go back to the immunologists and cell biologists to solve those fundamental problems, and bring solutions back to the human transplant program.”

Advances move fast in transplant medicine

The rapid creation of the Center for Translational Transplant Medicine is due, in part, to the immense growth of the MGTI since its creation in 2010. The Institute merged all organ transplant programs in the MedStar Health network and “in that short time, we have become a national leader in both volume and clinical outcomes,” says Fishbein.

With nine surgeons and more than 20 physicians, the institute transplants more than 300 solid organs a year at MedStar Georgetown University Hospital, and most of these transplants are abdominal organs — the bowel, pancreas, liver and kidneys.

Fishbein is known as one of only a handful of international experts on intestinal transplantation, and MGTI is now the second largest intestinal transplant in the country — all patients receiving a bowel have a small intestine transplant and one in four also have a transplant of the large intestine.

Advances in transplant medicine moves rapidly, he says. “What goes from bench to bedside really does occur within a couple of years.”

In fact, in only a few years, Fishbein has developed new immunosuppressive regimens, surgical techniques and other treatments to improve outcomes.

And Zasloff, a pioneer in innate immunity, has contributed to other clinical breakthroughs. For example, following an observation made by Fishbein, Zasloff uncovered the cause of some bowel failures in patients. He found that about 30 percent of patients with intestinal failure seeking intestinal transplants have a mutation in their NOD2 gene — the same mutation found in Crohn’s disease, an inflammatory intestinal disorder. This mutation impairs the ability of the innate immune system to protect the bowel against bacteria that led to the transplant, Zasloff says.

“That finding demonstrates that variation exists in human innate immunity,” he says. “If a person receiving a new bowel has the NOD2 gene mutation, the healthy new bowel will most likely, quickly fail. It isn’t rejection, per se — it is a genetic failure preventing the recipient to mount an effective innate response to microbes in the gut, which is why their intestines failed in the first place. The bowel was destroyed by the microbes because they weren’t suppressed properly,” Zasloff says.

“One way to solve that problem is to shore up the innate immune system in a way that overcomes the NOD2 genetic deficit in these patients, in order to avoid the risk of graft failure,” Zasloff adds. “In patients who are transplanted, we need to bolster their innate immunity to fight off microbes, while suppressing the adaptive immune response that leads to transplant failures.”

Fishbein says the approach to transplantation medicine has become personalized.

“One of the goals of the center is to use the powerful molecular tools we have to identify individuals who are at greatest risk of rejection due to their genetic inheritance,” Fishbein says. “There was a time when every patient was treated the same. They came in for a transplant, we looked at a few immune parameters, and that was it. Now we know there are genes we can focus on that may mean the difference between a successful transplant and one that will fail. And we need to apply these findings to all different organs being transplanted here.”

Zasloff is optimistic about the path forward.

“We will learn how to trick the immune system to ignore the new organ, and to bolster its natural innate response to pathogens,” Zasloff says. “We are just entering the era of transplant immunology, and this center has great potential to make a very big difference in the lives of our patients.”

By Renee Twombly, GUMC Communications