Mass. General transplant method prevents organ rejection

HARVARD UNIVERSITY, MASS GENERAL
Mass. General transplant method prevents organ rejection
By Patricia Wen, Globe Staff

A Massachusetts General Hospital research team is reporting a major advance in the years-long effort to overcome the rejection of organ transplants.

Four out of five patients who underwent an experimental kidney transplant were able to stop taking powerful immunosuppressive drugs, and they have so far lived between 15 months and almost five years without experiencing rejection. At the time of their transplant, the patients received bone marrow from the same donor.

The report in tomorrow's New England Journal of Medicine is considered particularly significant because the patients received kidneys that were different from their own tissue type. Transplants of such mismatched organs are the most common, and the most likely to be rejected, even when patients take immunosuppressive drugs.
One of the five patients rejected the kidney during the experimental program, and researchers ultimately concluded that was due to an unexpected antibody reaction. The team later tweaked their protocol to include a new drug to prevent such a scenario from happening again.

Dr. David H. Sachs, a 66-year-old Harvard Medical School professor who has spent his career trying to induce tolerance for organ transplants, said he was encouraged by his team's "initial success" with the procedure.

"While we need to study this approach in a larger group of patients before it is ready for broad clinical use, this is the first time that tolerance to a series of mismatched transplants has been intentionally and successfully induced," said Sachs, who co-authored the study with two transplant surgeons, Dr. Tatsuo Kawai and Dr. Benedict Cosimi, as well as a dozen other researchers at Mass. General.

Sachs, director of Mass. General's Transplantation Biology Research Center, has long believed that a donor's bone marrow -- from which immune cells originate -- could play a pivotal role in giving transplant patients "induced tolerance" to a donated organ.

Under Sachs' approach, five days prior to transplant surgery, patients begin low-dose chemotherapy to kill off some of their own marrow cells and make room for the injection of the donor's bone marrow.

The patients also receive a drug and radiation to the thymus to eliminate a type of immune system cell, known as a T cell, that typically attacks any tissue perceived as foreign.

On the day of the procedure, surgeons attach the new kidney while injecting the donor's bone marrow into a blood vessel in the patient's arm. The donor's bone marrow mixes with the patient's, creating a temporary state called "mixed chimerism." This tricks the patient's immune system into recognizing for years -- and possibly forever -- the donated organ as part of the "self."

After the surgery, the immune system is still in a period of adjustment, and doctors give patients anti-rejection drugs that are gradually tapered off. Most patients were off the drugs by the ninth month.

Sachs first tried this approach successfully on mice, pigs, then monkeys. In 1998, he won approval to try his treatment on a select group of Mass. General patients with severe kidney failure, all of whom were offered matching kidneys from close relatives. When these six patients did well, Sachs moved on to the most ambitious test of his method, trying it out on patients with mismatched donors.

Sachs' study represents a pivotal moment in organ transplantation, organ transplant researchers say. It shows that it may be feasible to eliminate immunosuppressive drugs with their debilitating side effects, such as skin warts, cataracts and increased risks of heart disease, diabetes and serious infections. Also, patients may no longer need to live with the fear of organ rejection. Within 10 years, half of all transplanted kidneys fail because of chronic rejection, a bleak predicament in this era of organ shortages.

"This is landmark work," said Dr. Joshua Miller, an organ transplant researcher from Northwestern University's Feinberg School of Medicine in Chicago. "It gives us hope that recipients of organ transplants will be relieved of being on chronic immunosuppressive drugs for the rest of their lives."

Researchers cautioned, though, that only the healthiest patients may be able to endure the rigorous pre-transplant treatments.