Stanford Report, October 18, 2000
proving successful in pediatric transplantation research
BY HEATHER ROCK WOODS
Pediatric surgeons and scientists are closing the distance between lab bench and patient bedside as they strive to give children needing transplants a chance at longer, healthier lives.
At Lucile Salter Packard Children's Hospital about 50 children per year benefit from liver and kidney transplants, making the hospital one of the busiest transplant centers in the country, with survival outcomes among the best in the world.
Liver transplant survival rates are 88.3 percent at one year, 83.8 percent after three years and 93 percent long-term for children who receive livers from living donors. Kidney survival rates are nearly 100 percent at one year and 95 percent after two years. All of these rates rank far above the national averages reported by the United Network for Organ Sharing.
Carlos O. Esquivel, MD, PhD, chief of the division of transplantation and director of the liver transplant programs at Stanford and Packard, attributes the success of the pediatric liver program to a dedicated medical team, a hospital environment conducive to kids, excellent outcomes, and an innovative union of clinical and experimental research.
Lab scientists and physicians interact closely to incorporate clinical observations into lab work and then translate those results back into better patient care and quality of life.
"The bench to bedside approach is special in pediatrics," said Alan M. Krensky, MD, chief of the division of immunology and transplantation biology. "We really have the kind of diseases that are amenable to this research."
Two key obstacles to transplantation are organ shortage and organ rejection. Esquivel has played a major role in addressing the former by creating and refining techniques to put organs to fullest use. After pioneering transplantation in babies, Esquivel introduced novel techniques to Packard's liver transplant program, such as using living liver donors and accomplishing split liver transplantation, in which a small portion of one liver goes to a child and the remainder is transplanted into an adult.
"The next frontier is artificial livers," Esquivel said. Initially, he suggests, an artificial liver would be an external way to perform the liver's function, similar to a dialysis machine for kidney failure. But eventually, a surgeon could go to the shelf and get a liver, Esquivel speculated. "We now understand better how cells and genes work; it's not so far out to think of an artificial liver."
So far, Esquivel has only discussed the idea, but with his new endowed position as the Arnold and Barbara Silverman Professor in Pediatric Transplantation, he hopes to begin a research collaboration to explore and develop the potential for artificial livers.
Organ rejection is the second key area of research. One's immune system tries to attack, or reject, a new organ because it is identified as foreign, as in the case of a flu virus. To prevent organ loss, patients are subjected to toxic drugs that debilitate their immune systems. This, unfortunately, allows infections and diseases such as cancer to thrive unchecked. Also, the side effects of the drugs themselves may be harsh, including growth and learning retardation and kidney damage.
A major research initiative is under way to avoid the need for immunosuppressive drugs altogether by teaching the body to accept the new organ through a process called tolerance. Krensky has already demonstrated a method that works in animals.
"There are lots of reasons that tolerance is the holy grail of transplantation and immunology," said Krensky, the Shelagh Galligan Professor in Pediatrics.
The body naturally uses tolerance everyday. The immune system's T-lymphocytes latch onto each particle they come across, identifying it as either "not-self" (and then launching an attack) or as "self" (and then leaving it alone). Krensky is exploring a way to teach the body immediately after surgery to recognize the new organ as self.
This line of research began from clinical observations that liver transplant patients had fewer problems with long-term chronic rejection than recipients of other organs did. Esquivel added that for children receiving combined liver and kidney transplants, the liver seems to protect the kidney from rejection.
"The liver has a magical property. It seems to induce tolerance," Krensky said. One explanation for this natural tolerance is that the liver makes HLA, a protein that coats the surfaces of organs, acting as a self-identity cloak. Thus, in transplants, the foreign HLA on the organ typically brands it a target for immune attacks. In the case of a transplanted liver, though, the new HLA tells T-lymphocytes to recognize the new liver and HLA as self.
Krensky has manufactured synthetic pieces of HLA in the lab. Given to animals for two weeks after a transplant, the synthetic HLA programmed T-lymphocytes to tolerate a new organ with no rejection. The animals never required immunosuppressive drugs, Krensky said. He added that early phase trials for human kidneys have shown an HLA drug to be safe and to have a positive effect although it did not induce tolerance because standard immunosuppressive drugs (which are still needed in an early phase clinical trial) block tolerance.
There are still safety issues to work out: researchers need to make sure that HLA does not create tolerance to any viruses or diseases that come with the donated organ.
"The experience with liver transplantation led to the tolerance lab research the bedside went to the bench. Now we're going from bench to bedside for kidneys," said Krensky, who added that liver patients should benefit in the future as well.
Tolerance is being tested first on kidneys because those patients have more treatment options, including dialysis and living relatives who can donate one of their two kidneys. People who need liver transplants are often far sicker. They also have no alternative such as dialysis, and to be a living liver donor is riskier.
The National Institutes of Health and the Juvenile Diabetes Foundation found tolerance so promising that last year they started the international Immune Tolerance Network. Krensky is one of three Stanford faculty members on the network steering committee. The network will develop protocols to induce tolerance and then conduct large-scale clinical trials for liver, kidney and pancreas transplantation, for autoimmune diseases such as juvenile diabetes and for allergies. HLA is one of a dozen approaches being considered.
"Transplants are life savers, but it's still a chronic condition," said Krensky. "Tolerance would be a cure."
"If we can understand the mechanism of rejection and induce tolerance, that would be incredible," added Esquivel. "Children would be able to lead normal lives."
Reprinted from Packard Children's News, a publication of the Lucile Packard Foundation for Children's Health. The foundation, established in 1996, is the dedicated fundraiser for Lucile Salter Packard Children's Hospital and the pediatric programs of Stanford's School of Medicine. Since its inception, the foundation has raised more than $78 million to support patient care, training and research.