The hand surgery, and the research that led to it, is one example of many innovative organ transplantation procedures spearheaded by U of L surgeons and scientists in conjunction with affiliated Louisville hospitals such as Jewish.

Preventing Rejection

"Hand transplantation is an extremely complex procedure," says surgical team leader Warren C. Breidenbach, a hand surgeon with Kleinert, Kutz and Associates and assistant clinical professor of surgery at U of L. "It could be at least a year before we know if he will have a good functioning hand."

A hand transplant, unlike a solid organ transplant, involves multiple tissues (skin, muscle, tendon, bone, cartilage, fat, nerves and blood vessels) and is formally called a composite tissue allotransplantation.

Well before the 18-member surgical team could consider such a procedure, a lot of research had to take place in U of L laboratories in conjunction with Kleinert, Kutz and Associates and Jewish Hospital.

The research focused on the intricacies of attaching complex tissues and strategies for preventing rejection. Anti-rejection drugs were tested in lab animals with transplants to gauge the procedure's feasibility.

"We didn't know a lot about hand transplants, nor did anybody else in the world," except that one attempted in Ecuador in 1964 failed after 14 days, says John Barker, U of L associate professor of surgery and head of the hand-transplant research team. "Doctors knew about organ transplants and hand replants-taking a person's own amputated hand and putting it back on-but nobody knew anything about transplanting a hand."

Members of the research team gave themselves two years to prove the viability of the hand transplant concept. Since skin is one of the most rejectable tissues in the body, a transplant would fail unless foreign skin rejection could be resolved.

Jon Jones, U of L assistant professor of surgery, says he was confident that the issue of skin rejection could be overcome. Jones, Barker and the research team worked in consultation with transplant surgeons, including Frederick R. Bentley, director of U of L's solid organ transplant program. The team tested drugs used for solid organ transplantation to see if they would be viable for the hand transplant. Their main concern was the toxic side effects of the immunosuppression drugs.

"They said 'no way are we going to give toxic drugs just to put a hand back on somebody,'" Barker says. "We would have to minimize the toxic side effects."

The research had to prove two main concepts: that drugs could provide the highest level of anti-rejection and that they could do so with minimal toxicity.

Jones led the research team that developed the drug regimen and tested it in laboratory animal models. Barker and Jones credit much of the research to fellows from U of L's plastic and reconstructive surgery division.

"That was the research that gave us the confidence that we could do this in humans and it would work," Jones says.

The interdisciplinary collaboration between hand surgeons and transplant surgeons, Jones says, will impact the future of transplantation and reconstructive surgery-not just for hand surgery, but for many types of transplantation.

New Approaches

To keep his hand, Matthew Scott will have to stay on organ rejection drugs-and withstand their possible side effects-for the rest of his life.

The next phase in organ transplantation will be to get rid of toxic anti-rejection drugs altogether. U of L's Challenge for Excellence research goals include the recruitment of faculty who can break through this final frontier.

The recent recruitment of Suzanne Ildstad, an internationally renowned organ transplant and immunology researcher, and her 40-member team that comprises the Institute for Cellular Therapeutics, is a step in that direction.

Although her work is not directly related to the hand transplant, Ildstad says she hopes to create genetically based and other therapies that will make cross-human and even cross-species organ transplantation possible without immunosuppressants.

Support for Ildstad's work will come from Kentucky's "Bucks for Brains" initiative and the Jewish Hospital Foundation. Each is contributing $4 million to an endowment.

"I saw it as a real strength that U of L was working in collaboration with Jewish Hospital and Norton Healthcare," Ildstad says. "There are already in place outstanding solid organ transplant and bone marrow programs. All the components for us to do our protocols were there."

The institute is scheduled to move into the new Baxter Biomedical Research Building this fall. Ildstad performed a controversial experimental surgery in 1995 to transplant baboon bone marrow into a man with AIDS, Jeff Getty. Since baboons can't get AIDS, it was theorized that the AIDS-resistant baboon stem cells might, with the help of facilitator cells, take root or "engraft" in human bone marrow to produce immune-system cells to fight diseases to which AIDS patients are prone.

Previously, such a procedure would have been impossible due to cross-species rejection, but discoveries made by Ildstad are making grafts between genetically mismatched donors and hosts possible.

Dr. Suzanne Ildstad

"We were the test case, so there was a lot of debate as to whether cross-species transplants should happen," Ildstad says.

Some scientists feared that mixing cells across species could form new diseases, but that did not happen. After two weeks, the baboon cells cleared out of Getty's body and many scientists judged the experiment a failure. But, Ildstad says, it proved that cross-species transplantation can be safe.

Getty, a health worker and AIDS activist, says he believes immunological approaches will be the key to defeating AIDS.

"The virus can mutate faster than we can throw drugs at it," he says. "We have to find that immunological component. That's why the bone marrow transplant was worth it."

Since the experiment, which has not been replicated, Ildstad has mainly worked on human-to-human transplantation-research that could impact the treatment of ailments as diverse as leukemia, heart disease, diabetes and sickle cell disease.

Immunology's Holy Grail

The key to Ildstad's studies is to find what causes transplants to fail. For her efforts, the 46-year-old Ildstad recently became one of the youngest researchers inducted into the Institute of Medicine of the prestigious National Academy of Sciences.

Many lives are lost each year as patients in need of transplants await scarce organs from genetically matched donors. A basic premise of Ildstad's work is that these deaths can be avoided if doctors can learn to fool the immune system into accepting donor organs and other tissue without the need for toxic anti-rejection drugs.

Several years ago Ildstad made a finding that promises to make successful human-to-human and maybe even animal-to-human transplants possible.

At the University of Pittsburgh in 1988, Ildstad followed up research on "mixed chimerism" she had done at the National Institutes of Health. The concept involves transplanting donor marrow into a host to create a hybrid immune system that would allow any organ from the donor to be transplanted without rejection.

In mixed chimerism studies in mice and rats, Ildstad discovered a "facilitating cell" that turned out to be the key ingredient in successful bone marrow grafting.

In treating leukemia patients it is standard practice to give bone marrow transplants to replace marrow lost to chemotherapy and radiation. An ongoing problem is graft-versus-host (GVH) disease, in which the donor marrow rejects the patient's body and attacks it. To avoid GVH, T-cells are typically removed from the marrow before transplant. Ironically this means the transplant is more likely to fail.

In preparing bone marrow for transplant, Ildstad discovered that the facilitating cells were being removed with the T-cells. When the facilitating cells were retained the success rate of the engrafts increased.

The find is leading to positive results in several disease studies.

Leukemia

In FDA-approved studies, Ildstad says her team has improved the process of treating bone marrow for transplant.

"In recent patients we should have had about an 80 percent chance of having severe graft-versus-host disease" had they received unmodified marrow, she says.

But with the modified marrow "there has been virtually no GVH-and these are patients who otherwise would not be eligible for a transplant because they didn't have a suitably matched donor," she says. "We know now for leukemia that we can find a match or a donor for people who otherwise don't have a donor."

Sickle Cell Disease

Ildstad is screening patients for a major study that will use a combination of radiation and bone marrow transplantation to treat sickle cell disease, a blood disorder that primarily afflicts African Americans.

"We just received our first NIH grant for using our technique to treat sickle cell disease," Ildstad says.

The study will begin with patients at Jewish Hospital, Kosair Children's Hospital and U of L Hospital and grow to include St. Jude Children's Research Hospital in Memphis, Tenn.

Bone marrow transplants are already being used to help restore healthy red blood cells to sickle cell patients, but Ildstad says she hopes refinements in the technique will further reduce patient mortality rates.

An Array of Research

The success of bone marrow transplant research also could lead to improvements in the transplantation of solid organs.

"It has been gratifying to see the work go from years of basic research to clinical applications," Ildstad says. "Two areas I'm especially excited about are the solid organ tolerance protocols that are under way for heart transplants and kidney transplants."

Work in these areas is slated to begin at U of L and Jewish hospitals. Heart work continues also at The Cleveland Clinic Foundation.

Students will also benefit from Ildstad's research. The institute has a large training program for postdoctoral fellows and graduate students, and a minority recruitment program is being planned, she says.

Ildstad believes in fast-track research. Nothing less than cures will satisfy her.

"When you're doing research, you don't know whether this will all work yet, but I have to believe it will work or I wouldn't be pursuing it," she says. "I'm optimistic."