Scientists Are Teaching the Body to Accept New Organs

Summer 2019
Patients receiving new kidneys and livers must take damaging anti-rejection drugs for the rest of their lives. Now researchers hope to train the immune system instead of just tamping it down.
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It was not the most ominous sign of health trouble, just a nosebleed that would not stop. So in February 2017, Michael Schaffer, who is 60 and lives near Pittsburgh, went first to a local emergency room, then to a hospital where a doctor finally succeeded in cauterizing a tiny cut in his nostril.
Then the doctor told Schaffer something he never expected to hear: “You need a liver transplant.”
Schaffer had no idea his liver was failing. He had never heard of the diagnosis: Nash, for nonalcoholic steatohepatitis, a fatty liver disease not linked to alcoholism or infections. 
The disease may have no obvious symptoms even as it destroys the organ. That nosebleed was a sign that Schaffer’s liver was not making proteins needed for blood to clot. He was in serious trouble. 
The news was soon followed by another eye-opener: Doctors asked Schaffer to become the first patient in an experiment that would attempt something that transplant surgeons have dreamed of for more than 65 years. 
If it worked, he would receive a donated liver without needing to take powerful drugs to prevent the immune system from rejecting it.
Before the discovery of anti-rejection drugs, organ transplants were simply impossible. The only way to get the body to accept a donated organ is to squelch its immune response. But the drugs are themselves hazardous, increasing the risks of infection, cancer, high cholesterol levels, accelerated heart disease, diabetes, and kidney failure.
Within five years of a liver transplant, 25 percent of patients on average have died. Within 10 years, 35 to 40 percent have died.
“Even though the liver may be working, patients may die of a heart attack or stroke or kidney failure,” said Abhinav Humar, a transplant surgeon at the University of Pittsburgh Medical Center who is leading the study Schaffer joined. “It may not be entirely due to the anti-rejection meds, but the anti-rejection meds contribute.”
Kidneys in particular may be damaged. “It is not uncommon to end up doing a kidney transplant in patients who previously had a lung or liver or heart transplant,” Humar added.
Patients usually know about the drugs’ risks, but the alternative is worse: death for those needing livers, hearts, or lungs; or, for kidney patients, a life on dialysis, which brings an even worse life expectancy and quality of life than does a transplanted kidney.

A Glimmer of Hope

In 1953, Peter Medawar and his colleagues in Britain did an experiment with a result so stunning that he shared a Nobel Prize for it. He showed that it was possible to “train” the immune systems of mice so that they would not reject tissue transplanted from other mice.
His method was not exactly practical. It involved injecting newborn or fetal mice with white blood cells from unrelated mice. When the mice were adults, researchers placed skin grafts from the unrelated mice onto the backs of those that had received the blood cells. 
The mice accepted the grafts as if they were their own skin, suggesting that the immune system can be modified. The study led to a scientific quest to find a way to train the immune systems of adults who needed new organs.
That turned out to be a difficult task. The immune system is already developed in adults, while in baby mice it is still “learning” what is foreign and what is not. 
“You are trying to fool the body’s immune system,” Humar said. “That is not easy to do.”
Most of the scientific research so far has focused on liver and kidney transplant patients for several reasons, said James Markmann, chief of the division of transplant surgery at Massachusetts General Hospital.
Those organs can be transplanted from living donors, and so cells from the donor are available to use in an attempt to train the transplant patient’s immune system.
Far more people need kidneys than need any other organ—there are about 19,500 kidney transplants a year, compared with 8,000 transplanted livers. And those transplanted kidneys rarely last a lifetime of battering with immunosuppressive drugs.
“If you are 30 or 40 and get a kidney transplant, that is not the only kidney you will need,” said Joseph R. Leventhal, who directs the kidney and pancreas transplant programs at Northwestern University.
Another reason to focus on kidneys: “If something goes wrong, it’s not the end of the world,” Markmann said. If an attempt to wean patients from immunosuppressive drugs fails, they can get dialysis to cleanse their blood. Rejection of other transplanted organs can mean death.
The liver intrigues researchers for different reasons. It is less prone to rejection by the body’s immune system. When rejection does occur, there is less immediate damage to the organ.
And sometimes, after people have lived with a transplanted liver for years, their bodies simply accept the organ. A few patients discovered this by chance when they decided on their own to discard their anti-rejection drugs, generally because of the expense and side effects. 
An estimated 15 to 20 percent of liver transplant patients who have tried this risky strategy have succeeded, but only after years of taking the drugs.
In one trial, Alberto Sanchez-Fueyo, a liver specialist at King’s College London, reported that as many as 80 percent could stop taking anti-rejection drugs. In general, those patients were older—the immune system becomes weaker with age. They had been long-term users of immunosuppressive drugs and had normal liver biopsies.
But the damage caused by immunosuppressive drugs is cumulative and irreversible, and use over a decade or longer can cause significant damage. Yet there is no way to predict who will succeed in withdrawing. 

Tricking the immune system

The more researchers learned about the symphony of white blood cells that control responses to infections and cancers—and transplanted organs—the more they began to see hope for modifying the body’s immune system. 
Many types of white blood cells work together to create and control immune responses. A number of researchers, including Markmann and his colleague, Eva Guinan of the Dana-Farber Cancer Institute, chose to focus on cells called regulatory T lymphocytes.
These are rare white blood cells that help the body identify its own cells as not foreign. If these regulatory cells are missing or impaired, people can develop diseases in which the body’s immune system attacks its own tissues and organs.
The idea is to isolate regulatory T cells from a patient about to have a liver or kidney transplant. Then scientists attempt to grow them in the lab along with cells from the donor. 
Then the T cells are infused back to the patient. The process, scientists hope, will teach the immune system to accept the donated organ as part of the patient’s body.
Thomson“The new T cells signal the rest of the immune system to leave the organ alone,” said Angus Thomson, director of transplant immunology at the University of Pittsburgh Medical Center.
Markmann, working with liver transplant patients, and Leventhal, working with kidney transplant patients, are starting studies using regulatory T cells.
At Pittsburgh, the plan is to modify a different immune system cell, called regulatory dendritic cells. Like regulatory T cells, they are rare and enable the rest of the immune system to distinguish self from non-self. 
One advantage of regulatory dendritic cells is that researchers do not have to isolate them and grow them in sufficient quantities. Instead, scientists can prod a more abundant type of cell—immature white blood cells—to turn into dendritic cells in petri dishes.
“It takes one week to generate dendritic cells,” Thomson said. In contrast, it can take weeks to grow enough regulatory T cells.
The regulatory T cells also have to remain in the bloodstream to control the immune response, while dendritic cells need not stay around long—they control the immune system during a brief journey through the circulation.
“Each of us is taking advantage of a different approach,” Markmann said. “It is not clear yet which is best. But the field is at a fascinating point.”
What about patients who already had an organ transplant? Is it too late for them?
“I get asked that question almost every day I am seeing patients,” Leventhal said.
For now, the answer is that it is too late. These patients are not candidates for these new strategies to modify the immune system. But researchers hope that situation will change as they learn more.

“Someone has to be first.”

When Michael Schaffer, the Pittsburgh patient, was told that he needed a liver and that he could be the first patient in the group’s clinical trial, he shrugged. “Someone has to be first,” he said.
Schaffer began a search to find a living donor, a close relative willing to undergo a major operation to remove a lobe of liver—or a stranger whose cells were compatible and who was willing to donate. 
The Pittsburgh scientists told him how to proceed. Ask immediate family, then relatives, friends, and colleagues. If that failed, he would have to start advertising with fliers and posts on Facebook.
Schaffer is one of eight brothers. Four were older than 55, too old to safely undergo removal of part of their liver. The three younger brothers were in poor health.
He moved on to nieces and nephews. Three agreed to donate, and one, Deidre Cannon, 34, who was a good match, went forward with the operation.
It took place on Sept. 28, 2017. Afterward, Schaffer was taking 40 pills a day to prevent infections and to tamp down his immune system while his body learned to accept the new organ. 
But now he has tapered down to one pill, a low dose of just one of the three anti-rejection drugs he started with. And doctors hope to wean him even from that.
His case may be intriguing, but he is just one patient. The scientists plan to try the procedure on 12 more patients and, if it succeeds, to expand the study to include many more patients at multiple test sites.
For Schaffer, it has all been worthwhile. He is active, working with a teenage grandson to replace the tiles on his kitchen floor. He shovels snow and mows lawns as a favor for his neighbors, and helps take care of his grandchildren after school.
“My goal is to live to be 100 and get shot in bed by a jealous husband,” Schaffer said.

Master Conductors

In late 1989, transplant giant Thomas Starzl invited a Scottish immunologist named Angus Thomson, one of the few people in the world other than Starzl studying the anti-rejection drug FK506 (now called tacrolimus), to visit Pittsburgh. Yet what Thomson would concentrate on for decades to come was another interest of Starzl’s. 
Around the time that Thomson visited, Starzl had proposed that donor immune cells that came along with a transplanted organ might have helped some long-surviving transplant recipients delay or avoid rejection. The hypothesis was contrary to the prevailing view that donor immune cells instigated rejection. But Thomson, now Distinguished Professor of Surgery and Immunology, thought that Starzl was onto something and accepted his invitation to join the faculty at Pitt.
Throughout the next two decades, Thomson and his team studied donor regulatory dendritic cells (DCregs)—immune cells now thought to be important in moderating how a transplant recipient’s immune system responds. He calls dendritic cells the “conductors of the immunological orchestra,” because they can dictate how other immune cells behave.
HumarIn collaboration with Abhinav Humar, Pitt’s Thomas E. Starzl Professor of Transplantation Surgery and clinical director of the Starzl Transplantation Institute, Thomson’s lab also demonstrated in animal models that DCregs derived from organ donors could control the immune system of transplant recipients and prolong donor organ survival.
In 2017, with funding from UPMC’s new Immune Transplant and Therapy Center, Thomson and Humar started a clinical trial that would transplant liver lobes and DCregs from living donors. Michael Schaffer (featured above) became the first person in the world to receive DCregs from a donor. “It was a humbling moment,” says Thomson, “one that 20 years ago I would not have imagined would happen.” 
Schaffer is doing well and slowly being weaned off anti-rejection medications. And as this magazine went to press, 11 other patients had successful transplants as part of the trial.  —Arvind Suresh