Stem cells help doctors conduct breakthrough, drug-free organ transplants. Every day, many people die because of organ failure. Across the world, hundreds of thousands need organ transplants just to stay alive.
Some of these people were born with structural abnormalities like congenital heart defects or biliary atresia. Some were born with diseases that cause their organs to fail. Others develop diseases like cardiomyopathy that cause their organs to malfunction over time.
In the United States alone, over 100,000 people need an organ transplant in order to stay alive. While there’s a dire shortage of organ donors, some will be lucky enough to find one. But even after organ transplantation, their problems don’t end.
A key setback is that the body itself targets the newly transplanted organ as a foreign invader and attacks it. To prevent this from happening, patients have to take powerful drugs to suppress their immune systems. Without these medications, a transplanted organ that’s incompletely matched will be rejected, and patients have to go through a repeat transplant or face death. Those who receive donor kidneys can go on dialysis to support the new kidney, but eventually that fails too.
More commonly, transplant survivors face a lifetime of taking anti-rejection drugs — typically 15 to 20 pills a day. But they’re dangerous, costly and not always effective.
People taking immunosuppressant drugs become vulnerable to infection, diabetes, hypertension and cancers. These drugs are so toxic; they often overwhelm the transplanted organ. They’re also expensive, costing as much as US$20,000 a year, even with genetic versions.
A new study offers transplant patients the hope of doing away with these drugs.
The new findings show that patients who receive even a less-then-perfectly matched organ don’t reject it when they also undergo a second transplantation — this time of the organ donor’s stem cells, which are also imperfectly matched.
Researchers from the University of Louisville’s Institute for Cellular Therapeutics and the Chicago’s Northwestern Memorial Hospital report that, a year after receiving transplanted kidneys, the majority of patients in their pilot study stopped needing anti-rejection medicines.
The findings of their research, published in the March 7 issue of the journal Science Translational Medicine, will have a “major impact” on transplant science, the researchers say.
“It’s almost surreal when I think about it because I feel so healthy and normal,” says 47-year-old Lindsay Porter from Chicago, one of the transplant patients who participated in the study. “I hear about the challenges recipients have to face with their medications and it’s significant,” she adds.
The study has its limitations: It’s preliminary and it only involved a tiny number of patients. Also, the required procedure is expensive. Most importantly, its long-term effects still aren’t known.
But if it’s proven to work, the new process is a potential game-changer in the field of transplantation.
It’s the first to use a transfusion of a stem cell mixture to trick the body’s immune system into accepting organ transplants that it would normally reject.
“It’s a huge step forward,” says Dr. Suzanne Ildstad, University of Louisville’s Institute for Cellular Therapeutics director and co-author of the new study. “We’re really excited about it,” she says, adding that the next step would be to determine if the procedure would work for other kinds of organs — livers and pancreatic islet cells — between similarly mismatched donors and recipients.
What do the findings mean?
• The new research would improve the lives of transplant patients greatly by freeing them of a lifetime reliance on anti-rejection drugs, says transplant surgeon Dr. James F. Markmann of Massachusetts General Hospital, who was not involved in the study.
• It could mean that transplant patients in the future may need to take anti-rejection drugs only briefly, instead of taking them their lifetime.
• Those who rely on these meds now could discontinue them safely.
• It may even ease the shortage of transplantable organs by reducing the number lost to rejection, says Dr. Markmann. Due to a donor shortage, 4,573 U.S. patients died while awaiting a kidney transplant in 2008 alone, the National Kidney Foundation says.
• Thousands of people waiting for kidneys, as well as other organs — hearts, lungs, livers and pancreases — could also benefit from access to a wider organ pool.
• What’s more, the authors believe their work could allow the “retroactive treatment” of transplant patients — at least those with new kidneys — who are living with imperfectly matched organs. If their donors are still alive and willing to donate stem cells, then they could undergo the bone marrow transplant to save themselves from more years on immunosuppressants.
• The new protocol developed could be used to treat other diseases – leukemia, lymphoma and blood cancers — that require bone marrow transplants and improve the lives of these patients. Now a standard therapy for leukemia and lymphoma and for other diseases of the blood and bone, transplants of bone marrow stem cells are largely successful, but in many cases, the donor stem cells are rejected as incompatible.
• The new findings could mean that doctors could use bone marrow samples that today are rejected as incompatible.
• The finding thus open up the pool of those who could donate stem cell transplants to patients fighting blood cancers. “This opens up bone-marrow transplants to virtually any patient out there with a hematological condition” such as leukemia or sickle-cell anemia, says Dr. Tisdale, a hematologist at the U.S. National Heart, Lung and Blood Institute in Bethesda, Maryland. Right now, many of the 6,000 patients yearly who have a stem cell transplant “have to look far and wide for a perfect match,” Dr. Markmann adds.
That’s what the findings will mean — if the technique is proven safe and successful in a larger group of people.
Right now, immune cells from an unrelated donor often end up attacking the transplant recipient’s tissue in what is known as graft-versus-host disease (GvHD), a common and often fatal complication of bone-marrow transplantation.
And that’s exactly where Dr. Ildstad’s team started out.
The blood marrow transplantation the study participants were put through didn’t only allow them to accept kidneys from imperfectly matched donors without the need for drugs to suppress their immune system — it was also a significant feat in itself.
It was the first time that scientists have been able to replace people’s bone-marrow-derived stem cells completely with those from unrelated donors without causing GvHD1.
Tricking the immune system
Carried out at the University of Louisville in Kentucky and the Northwestern Memorial Hospital in Chicago, the study involved eight patients with kidney failure.
Their transplants came from living donors, who also underwent procedures to draw stem cells from their blood. In four cases, the donor was related to the recipient, but the organs were from less-than-perfect matches, varying from minimal to extreme: one patient’s kidney matched five out of six “human leukocyte antigens” or HLAs, while others had no more than three compatible HLAs.
Dr. Ildstad’s team first prepared patients with whole-body radiotherapy and several days of chemotherapy to suppress their immune systems and make space in their blood for the donor immune cells.
Then the kidney transplants were conducted and two days after, patients received a second transplantation of bone marrow. Bone marrow — the soft fatty tissue inside bones — contains immature blood-forming stem cells that give rise to all blood cells, including immune system cells.
The second transplantation was similar to a bone marrow transplant in almost every way, except that the researchers defied a cardinal rule: to never transfer an incompatible HLA match from one person to another, because this usually led to rejection of the bone marrow.
But despite flouting this rule, none of the study participants died and five even developed tolerance for their new kidneys.
Inducing chimerism with a new class of cells
Why did this happen? Why weren’t the kidney’s rejected?
Dr. Ildstad’s team says it’s because patients weren’t given ordinary stem cells from the kidney donors, but bioengineered cells. Donor bone marrow stem cells had been “tweaked” to induce “chimerism” — or the state in which dissimilar tissue is accepted by an immune system as its own.
The researchers say this was done by mixing the donor stem cells with a new class of cells — unrecognized until now — which they called “tolerogenic graft-facilitating cells.”
These “facilitating cells” were in fact extracted from kidney donors a month before transplant surgery. At that time, the donors were asked to inject themselves for several days with a medication that forced stem cells and the “facilitating cells” into their bloodstream. Researchers then collected these and sent off to the University of Louisville for processing.
The “facilitating cells” are naturally occurring cells that help create a more favorable environment for the stem cells and allow engraftment to occur safely, claims Dr. Joseph Leventhal, a transplant surgeon at the Northwestern Memorial Hospital where the transplants took place and a study co-author.
Dr. Ildstad has developed a process for enriching these cells and formed a company, Regenerex LLC, to patent technology. The company is based in Louisville.
After transplantation, the patients were sent home with strict instructions to avoid exposure to sick people and germs until their new, chimeric immune system stirred to life. They were given the same immunosuppressants that all transplant patients get, but these were reduced then completely withdrawn over time.
• One patient eventually rejected the organ and got another.
• Two had to resort to immunosuppressive drugs to stave off organ rejection.
• But five achieved “complete chimerism” and a year later were weaned off their immunosuppressants and have since shown no signs of rejecting the kidneys in follow-ups at six months and 20 months.
These patients — two women and three men from 35 to 46 years of age — were even the ones who received the least compatible kidneys among all study participants.
The new technique draws on research by two 1960 Nobel laureates: Australian immunologist Sir Frank Macfarlane Burnet and Brazilian-born British zoologist Peter Medawar, the Reuters Health reports. The two men won the Nobel for discovering that the immune system in animals can be trained to acquire tolerance of foreign tissue.
But it’s taken many years of research to make this happen in people, Dr. Leventhal tells Reuters.
“The idea here is to try to use donor-derived stem cells to achieve engraftment, a state we call chimerism,” Leventhal says. “Here what we are trying to do is get donor and recipient cells to peacefully coexist in the transplant recipient.”
Uncertainties over secrecy and safety
For most scientists who were interviewed by news agencies a few days after the breakthrough study, the study is indeed a “big deal.”
Dr. Abraham Shaked, chief of the University of Pennsylvania’s Department of Transplantation Surgery, who wasn’t involved in the study, called the results “absolutely remarkable” and “beyond any expectations.”
“Few transplant developments in the past half century have been more enticing,” write pioneer transplant surgeons James F. Markmann and Tatsuo Kawai of Massachusetts General Hospital, in a commentary accompanying the study’s publication. If borne out, the findings “may potentially have an enormous, paradigm-shifting impact on solid-organ transplantation,” they say.
But most scientists also pointed out the study’s uncertainties and limitation.
No control group was used. While the findings are “amazing” and a “big deal,” Dr. Kawai points out that the study did not involve a control group of patients undergoing the back-to-back transplantation of kidney and bone marrow without getting the enriched “facilitating cells.” Because of this lack it’s hard to tell how much of the success was due to the “facilitating cells.”
The study’s safety is questionable. The safety of the procedure also still needs to be confirmed, he tells Health Day News — then goes on to point out that it’s impossible for other scientific teams to replicate and test the research result because these cells aren’t fully described in the paper. Dr. Kawai is a transplant specialist and associate professor of surgery at Harvard Medical School.
In a controversial move to protect their commercial interest in the newly described therapy, Dr. Iliad’s team had not disclosed much about the “facilitating cells,” the method used to isolate these, or how they were identified and treated. But the researchers reported that earlier studies in mice revealed the existence of these facilitating cells. Meanwhile, Dr. Iliad is seeking a way to commercialize the approach through her company, Regenerex.
The new procedure is risky. It’s Dr. Kawai’s opinion that the new transplant procedure remains “highly risky” for the moment and patients in the recent trial have taken too much risk. “Their approach is to totally destroy the host immune system by medication and radiation,” he points out.
In a separate study published in 2008 in the New England Journal of Medicine, Dr. Kawai and his colleagues at Harvard had also achieved temporary chimeric tolerance.
In that study, Dr. Kawai’s team didn’t suppress the patients’ immune systems with chemotherapy and radiation. Donor immune system cells were also allowed to die off after a few weeks. But 10 years after the transplant, at least one patient still has a working donor organ and doesn’t need to take anti-rejection medications.
Dr. Kawai tells Reuters he would like to see the new approach with “tolerogenic graft-facilitating cells” tested first in patients with blood cancers or other disorders who need a bone marrow transplant. This “harsh treatment” is justified in patients who have no other options, he says.
It’s not possible to replicate and test. A transplantation expert and author of a widely hailed recent study on chimerism also calls the results “very interesting … and very different from what others expected. But he notes that these “are not going to be easy to reproduce,” given the authors choice to keep the method of cellular preparation a secret.
That’s the opinion of Dr. David H. Sachs, director of the Massachusetts General Hospital’s Transplantation Biology Research Center.
“The question is: will these patients remain free of GvHD?” he asks. “You would hope that it’s true, but it’s a little early to claim that,” he tells Health Day News.
The methodology is flawed. Dr. John Tisdale, a hematologist at the U.S. National Heart, Lung and Blood Institute in Bethesda, Maryland, also praises the results of Dr. Ildstad’s study, but is critical of the methodology.
The methodology muddled the cause of the successful non-rejection of kidneys by patients, he says. Was this brought by the “facilitating cells” or the timing of the chemotherapy drug that was used to prevent graft rejection and GvHD? he asks. The question is difficult to answer, he notes, because all the study participants received the facilitating cells.
“The facilitating cell adds an extra level of complexity that might not be necessary,” Tisdale even adds.
Secrecy makes it difficult to test. Megan Sykes, Columbia Center for Translational Immunology director at Columbia University in New York takes issue with the secrecy shrouding the methodology.
“It’s difficult to assess something that doesn’t provide the key methodology,” she tells Health Day News. “Nobody is quite sure what these cells are.”