Fight against rejection
Until drugs that suppress the body’s immune response were introduced in the 1960s, most organ transplants failed.
“The drugs are wonderful,” says Dr. David Sachs, a professor of surgery at Harvard Medical School and director of the Transplantation Biology Research Center at Massachusetts General Hospital. “They made transplantation possible.”
The medications can prevent rejection of the organ that occurs even when it is matched by blood type and the six most important surface proteins, called HLA markers. But organ recipients must stay on the drugs for life -- and they sometimes can have severe side effects, such as bloating, tremors and kidney failure.
Now there may be an alternative -- at least for some kidney transplant patients. Two reports in the Jan. 24 issue of the New England Journal of Medicine detail methods that have allowed patients’ immune systems to accept their new organs without the long-term use of drugs.
Combining two immune systems
One of the studies came from a team at the Stanford University School of Medicine. Researchers there performed a kidney transplant between two brothers, followed by a transplant of bone marrow stem cells into the patient. In doing so, they achieved what’s known as a persistent state of mixed chimera -- something previously seen only in animal models.
In mythology, a chimera is a monstrous creature made of the parts of multiple animals. In biology, a chimera is an animal that has two or more populations of genetically distinct cells. The kidney transplant patient at Stanford became a chimera because his immune system was turned into a mixture of his and his brother’s.
On the day the patient received his transplant, he began a regimen of drugs and radiation that kept his body from rejecting his new kidney, while also increasing the number of a kind of immune cells that lead researcher Dr. Samuel Strober described as the “U.N. peacekeepers” of the immune system.
Two weeks later, the patient was given an injection of bone marrow stem cells that had been collected from his brother. “There was an immune war between the host and the donor,” Strober said, but the peacekeeper cells were there to mediate, giving both sides time to learn to accept each other. Donor immune cells that had been injected were trained not to attack their new home, while the recipient’s immune cells learned to accept both the new immune cells that were taking up residence and the new kidney.
The doctors slowly tapered the patient’s dose of immunosuppressive drugs over the course of six months. More than two years later, he is still off the drugs, and his new kidney is functioning well.
To this day, the patient’s immune system is a mixture of his and his brother’s. The patient is considered a “mixed” chimera because he has both types of immune cells in his body. He would be a complete chimera if his brother’s immune cells had completely taken over. This is what happens in leukemia patients who must have their bone marrow wholly replaced to beat their cancer. In complete chimeras, immunosuppressive drugs are still needed, but in this case it is to prevent the newly installed immune system from attacking its host.
So far, Strober’s team has tried the procedure in five other kidney transplant patients who have received perfectly matched organs. Three of these recipients may eventually be able to maintain their transplants without the use of immunosuppressive drugs, Strober says, though he cautions that all are still in the early stages of the study.
The group plans to continue its studies in a total of 15 patients during the next two years. After that, Strober said, the next challenge is to get the procedure to work in patients who cannot find a perfectly matched kidney.
Chimerism in partial matches too
On the other side of the country, at Massachusetts General Hospital, Sachs’ group is doing just that -- getting patients to tolerate kidneys that are only a partial match without the use of immunosuppressive drugs. His team’s report in the same, recent issue of the New England Journal of Medicine details its success in getting chimerism to develop in four of five patients who received combined bone marrow/kidney transplants.
Sachs’ group used a slightly different procedure than Strober’s. Instead of waiting until after the kidney transplant had occurred to condition the patients’ immune systems and transplant the bone marrow cells, they instead prepared the patients ahead of time and did both transplants simultaneously.
The end result was much the same -- the kidney transplant patients were able to get off of immunosuppressive drugs without rejecting their transplants. But in Sachs’ group, the patients’ immune systems were chimeras for only about three weeks. After that, doctors could no longer detect the donors’ immune cells in the recipients.
Sachs says that it is not clear why his patients had mixed immune systems for only a short period of time, or how this is sufficient to induce tolerance and allow them to get off of the immunosuppressive drugs. It’s possible, he said, that the donors’ cells are in fact still in the recipient, but at low levels that cannot be detected.
Regardless of how things are working, Sachs says, “the kidney is in place and working.”
Sachs says it’s important that his team was able to get chimerism and tolerance in transplants that “intentionally crossed the HLA barrier,” meaning that the donors and recipients were only partially matched. Most transplant patients are not fortunate enough to find a complete match as a donor.
Sachs and his group are planning to study 20 more patients at Massachusetts General Hospital during the next three years. They then hope to expand their study to patients at multiple medical centers. Members of Sachs’ team are also working in the lab to expand their work to other organs and organs recovered from deceased donors.
Sachs’ group is also conducting early laboratory experiments to see whether combined transplants of bone marrow and kidneys might allow people to accept and tolerate xenografts -- organ donations from animals. Sachs says he is interested in this because getting those patients who are fortunate enough to find donors off of immunosuppressive drugs “won’t do anything for the organ shortage” that keeps so many others from ever having a chance.
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And then there’s the cost
The need to improve tolerance of transplanted organs goes beyond the inconvenience and side effects of immunosuppressive drugs.
For starters, the drugs don’t always prevent rejection that takes place slowly, over the course of five to 10 years, causing many patients to eventually lose their donated organs.
Then there’s the cost factor.
The standard immunosuppressive drug cocktail for kidney transplant patients costs around $15,000 per year, according to a website for the PKD Foundation, an advocacy group for patients with polycystic kidney disease, more than 60% of whom eventually need kidney transplants.
A cost-benefit analysis by Dr. T. Kawai, the first author of the Massachusetts General Hospital study, showed that the upfront costs of the procedure used in that research could be about $45,000 more than a traditional kidney transplant because of the simultaneous bone marrow transplant. But, the analysis found, the cost of immunosuppressive drugs and treatments for complications from the drugs can easily surpass that amount in five years.
-- Erin Cline Davis
