Stimulating Stem Cells from Bone Marrow Prevents Rejection of Transplanted Livers

Patients who need new organs and receive a transplanted organ must take anti-rejection drugs for the rest of their lives. These drugs suppress the immune system and cause the patient to be susceptible to various infections and cancers. However, researchers from The Johns Hopkins University have developed a technique to stimulate stem cells in the body of a rat after a liver transplant that prevents rejection of the new organ without the need for lifelong immunosuppressive drugs.

In this procedure, researchers transplanted portions of the livers from dark agouti (DA) rats into another rat strain (Lewis-type). After the transplant, they gave the rats a seven-day treatment of low-dose tacrolimus (an immunosuppressant, trade name is Prograf), or plerixafor (a stem-cell stimulator, the trade name is Mozobil) or a combination of the two drugs. They only gave a very low, short-term dose of the immunosuppressive drug (that prevented immediate immunological rejection of the liver), and four doses of the medication that mobilizes bone marrow stem cells in the recipient’s body. These mobilized stem cells seek out and populate the donor organ. The stem cells also hold the immune response at bay and prevent rejection of the transplanted liver. Twelve of the 13 rats that received a combination of the two drugs 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. The surviving rats had not received any immunosuppressive drugs other than the initial low-dose treatment for one week. Essentially, the Hopkins research group transformed the donor liver from a foreign object under attack by the rat’s immune system into an organ tolerated by the recipient’s immune system — all in a matter of three months from the date of transplant. Presently, this same research group is 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 leader of this study, Zhaoli Sun, associate professor of surgery at the Johns Hopkins University School of Medicine, said: “It is the dream for all scientists in the transplant field to erase the need for lifelong immunosuppressant drugs. Currently, if a patient survives for 10 or 20 years with a new liver, that organ is still seen as foreign inside its new body because immunosuppression puts blinders on the immune system that must stay on to prevent rejection. Our idea was to find a way to turn that organ into something that ‘belongs’ and is never at risk of rejection.”

Thousands of people with end-stage liver disease have received lifesaving liver transplants, but transplant rejection remains a chronic risk for these patients. Anti-rejection drugs also are quite expensive and increase the chance of developing severe infections and many kinds of cancers. Also, because anti-rejection drugs tend to cause patients to feel poorly, many patients are not compliant with their drugs, which is to say that they do not take them regularly.  Because anti-rejection drugs must be taken every day, failure to comply increases the risk of rejection of the transplant.  Typically, organ transplant recipients receive full doses of immunosuppressant drugs, such as tacrolimus, immediately after they receive new livers, since without these drugs, rejection would quickly result and patient would die.

The Lewis rats in this experiment received the equivalent of one-tenth the standard dose of tacrolimus.  The main goal was to induce some tissue rejection by the new liver, but not enough to kill it.  This “controlled rejection,” appears to create injury signals in the body that signal for stem cells to move from the bone marrow to the organ and repair the damage.  The stem cells also prevent the new liver from regenerating itself with cells from the donor because those cells are under attack by the recipient’s immune system.  This leaves an opening for the recipient’s stem cells to populate the liver and regenerate the liver.

Sun and his colleagues used plerixafor, a relatively new drug, which is known to free stem cells from the bone marrow and release them to circulate in the bloodstream. The drug is currently approved for patients about to undergo chemotherapy whose stem cells are harvested frozen and then returned to the body after cancer treatment. Many of these stem cells travel to the damaged liver and repopulate it with cells from the recipient, slowly taking over for the donor cells. The mechanism that brings the stem cells into the liver is becoming better understood, while the mechanisms by which stem cells become liver cells remain elusive. The stem cells also appear to modulate the immune response by increasing the number of regulatory T-cells, which helps reduce the chances of rejection.

Sun said, “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. 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 jump started 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, but 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.