JOHNS HOPKINS (US) — Researchers working with rats have developed a way to trick the body into accepting a transplanted liver without a lifelong regimen of anti-rejection drugs.
The method involves coaxing the recipient’s own bone marrow stem cells into becoming part of the transplanted organ, thus masking its foreign origins. The stem cells transform the donor liver from a foreign object into an organ tolerated by the immune system as little as three months after transplant.
The need to prevent rejection with immunosuppressant drugs, which have serious side effects, is currently a major obstacle to successful long-term transplant survival in humans.
“It is the dream for all scientists in the transplant field to erase the need for lifelong immunosuppressant drugs,” says study leader Zhaoli Sun, associate professor of surgery at Johns Hopkins University.
“Currently, if a patient survives for 10 or 20 years with a new liver,” he says, “that organ is still seen as foreign inside its new body. . . . Our idea was to find a way to turn that organ into something that ‘belongs’ and is never at risk of rejection.”
The researchers are also testing the method on other transplanted organs, including kidneys, in rats and other larger animals.
The technique, if replicated in humans, could mark a major shift in the process of organ transplantation, the researchers say. An article describing the experiment appears in the current issue of the American Journal of Transplantation.
Although thousands of people with end-stage liver disease have gotten lifesaving liver transplants in recent years, rejection remains a chronic risk. The expensive immunosuppressant drugs patients now need increase the chance of developing severe infections and many kinds of cancers.
The researchers transplanted portions of the livers of one kind of rat (dark agouti, or DA) into another (Lewis-type). For seven days after transplantation, the Lewis rats were treated with low-dose tacrolimus (an immunosuppressant), plerifaxor (a stem-cell stimulator) or a combination of the two. Twelve of the 13 rats that received the drug combination had long-term liver function and survived more than 180 days, while nearly all of the remaining rats rejected their new livers after 12 days.
“This short-term treatment had long-term results,” says Sun.
Typically, organ transplant recipients receive full doses of immunosuppressant drugs, such as tacrolimus, immediately after they receive new livers. Otherwise, rejection quickly results and patients may die.
Sun and his colleagues gave the Lewis rats in their experiment the equivalent of one-tenth the standard dose of tacrolimus. The goal was to have the new liver experience some mild rejection, but not enough to kill it. This “controlled rejection,” Sun says, appears to create injury signals in the body that cry out for stem cells to come and repair the damage being done to the new liver.
It also prevents the new liver from regenerating itself with donor cells because it is under immunologic attack, leaving an opening for the recipient’s stem cells to jump in and play that role.
Sun and his colleagues used plerifaxor, a relatively new drug, to free stem cells from the recipient’s bone marrow and release them to circulate in the bloodstream. Many of the stem cells traveled to the damaged liver to repopulate it with cells from the recipient, slowly taking over for the donor cells.
“In our study, the risk of organ rejection is eventually eliminated because the liver is no longer a foreign object, but comprised of many of the recipient’s own cells,” Sun says. “Once the recipient’s stem cells take over, the body sees the regenerated liver as its own and works to protect it, not attack it.”
Within three months, Sun and his colleagues found that the majority of the liver cells in the transplanted organ belonged to the recipient, not the donor. When they used whole livers instead of partial livers, the process took a year. This suggests that the transformation process is jumpstarted by using partial livers for transplant, because the organ already “needs” to regenerate itself to most effectively function, he says.
Sun cautions that clinical trials with human organ transplant patients might be years away, and then only if further research in animals confirms the method’s safety and value. The technique might prove useful not only at the time of a new transplant, but even after years of immunosuppressant drug use.
This research was supported by grants from the National Institutes of Health and Genzyme Inc.
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