Published online 23 January 2008 | Nature | doi:10.1038/news.2008.521

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Immune system trained to tolerate transplanted organs.

Transplanting part of the immune system along with an organ can help to prevent rejection. AJ PHOTO / SCIENCE PHOTO LIBRARY

Three independent research teams have successfully performed organ transplantations that do not require the recipient to face a lifetime of immunosuppressant drugs to prevent rejection. Instead, the new techniques prevent rejection by training the immune system to recognize the new organ as its own.

The three studies, published this week in the New England Journal of Medicine, are preliminary and involve only a few patients. But if the techniques can be reproduced in a larger population, they could eliminate one of the most enduring scars of the operation: the need to continue taking sometimes-dangerous immunosuppressant drugs.

Thousands of kidney transplantations are performed every year, and nearly 99% of patients in the United States are still alive a year after the surgery. But even when the organ donor is a close relative, the transplant recipient often needs to take immunosuppressant drugs for the rest of their lives to guard against organ rejection. But although the drugs help to prevent rejection, they also increase the risk of infection and are very pricey.

Previous work in animals has suggested ways to avoid taking these drugs. Mice and monkeys given an organ transplant coupled with an infusion of blood stem cells could sometimes be weaned off the immunosuppressant drugs1,2.

Blood stem cells are made by bone marrow and give rise to white blood cells, including the B cells that produce antibodies, and T cells that are important in distinguishing host from donor. Researchers found that transplanting these cells into the host created a hybrid immune system. The transplanted organ was no longer recognized as foreign; it was partly ‘self’.

Take over

The new reports all follow this principle, although not the same procedure.

Michael Stormon of the Children’s Hospital at Westmead in Sydney, Australia and his colleagues report on a liver transplantation in a 9-year-old girl with hepatitis3. Her illness, plus a virus she carried called cytomegalovirus, and the immunosuppressant drugs she was given after the operation, had weakened her own immune system so much that her immune cells were almost completely replaced by stem cells brought in by the donated liver. She even had to be re-vaccinated against the measles and the mumps, as the donor had not been vaccinated against them. The girl was able to discontinue her immunosuppressant regime a year after the procedure, and has not experienced any complications in the four years since.

Samuel Strober of Stanford University in California and his colleagues created a similar situation in a patient who received a kidney from his brother4. The patient was treated with radiation and a drug that destroyed his T cells. He then received a new kidney and an infusion of blood that had been enriched for blood-producing stem cells, both from his brother. Genetic tests revealed the presence of the brother's immune cells still circulating in the host’s blood more than two years after the procedure. The patient stopped taking immunosuppressant drugs with no signs of rejection.

Finally, David Sachs of Massachusetts General Hospital in Boston and his colleagues report on transplantations of kidneys and bone marrow in five patients whose donors were not related to them, making rejection more difficult to avoid5. Of the first three patients to undergo the procedure, one patient’s antibodies rejected the organ in the first attempt; the second attempt, however, was successful. Because of this, the researchers added an extra drug to their protocol to destroy the host's antibody-producing B cells in the following two patients. All four of the patients with successful initial transplants were able to discontinue their immunosuppressants in less than a year after the procedure.

Surprisingly, these patients did not continue to produce donor immune cells. Precisely why these patients did not reject their new kidneys is unclear, says Sachs.

Risk–benefit analysis

Bone-marrow transplantation carries its own risk, but the benefits may outweigh that, says Strober. “The short-term potential risks have to be put up against the long-term risks and the side effects and costs of the drugs,” he says. The researchers are preparing to continue the study in more patients. Strober says that if all goes well, the technique could be generally available in five to ten years.

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All three of these studies illustrate an emerging understanding of how the immune system can be trained to tolerate foreign cells, says Thomas Starzl, an immunologist and transplantation specialist at the University of Pittsburgh in Pennsylvania. Researchers have been transplanting organs successfully for forty years without fully understanding how the immune system responds, he says.

“No one understood what the mechanism of tolerance was,” says Starzl — nor the way in which organs became knitted into the recipient's body. By understanding those mechanisms, it becomes possible to adjust procedures to get the best benefit, he says.