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Stanford Report, June 28, 2000

Helping the immune system accept transplanted organs

BY MITCH LESLIE

Every organ transplant recipient owes his or her life to drugs that muzzle the immune system and prevent it from destroying the transplant. But by undermining the body's defenses, the same drugs make patients vulnerable to infections and cancer. Now a Stanford study suggests that proteins that disrupt communications within the immune system may allow doctors to slash the dose of these drugs, leaving patients with a stronger immune system better able to resist infections.

The proteins, which are types of monoclonal antibodies, prevent the foot soldiers of the immune system from receiving their orders to attack. But unlike older immune-suppressing drugs, monoclonal antibodies are specific, inhibiting only the cells targeted at the transplanted organ.

Immunosuppressant drugs are vital to keep the immune system from quickly destroying a transplanted organ. "If you transplant a kidney and do no form of treatment, the transplant will be non-functional within seven to nine days," said Bernard Hausen, MD, PhD, senior research scientist in transplantation immunology and lead author on the study. Suppressing the immune system spares the organ but opens the doors to harmful bacteria, viruses and parasites, and may allow cancer cells lurking within the body to spread. "Globally suppressing the immune system always reduces its ability to deal with pathogens," Hausen said.

For decades, scientists have dreamed of a more precise alternative: manipulating the immune system to induce tolerance. "Tolerance is a magic word ­ it means that we can accept a foreign body such as an organ without the need for immunosuppressive drugs," Hausen said. To produce tolerance, scientists must find a way to inhibit the immune attack on the transplant without compromising the remainder of the body's defenses ­ no simple task.

One strategy that shows early promise involves blocking the immune system's "attack" message. Immune system warriors called T cells actually launch the assault on a transplant, but they must first receive orders from another kind of immune cell known as an antigen-presenting cell (APC). When these two kinds of cells meet, they embrace, and two protein receptors on the surface of the APC interlock with matching receptors on the T cell. Without this double handshake, the T cell doesn't "know" to attack its target.

To interfere with this vital meeting, scientists at the Genetics Institute in Cambridge, Mass., designed monoclonal antibodies that latch onto these protein receptors on APCs and prevent them from joining with the receptors on T cells.

Tests with mice showed that these monoclonal antibodies sometimes produced tolerance but that there was an unfortunate side effect: immunosuppressant drugs like cyclosporine reduced the effectiveness of the antibodies. These results created a dilemma, Hausen explained. Knowing how fast the immune system can demolish a transplant, no scientist is going to give antibodies to organ recipients without backup of a conventional immunosuppressant. But if the two treatments counteract one another, the true efficacy of the antibodies may not become evident.

But what's true in mice is not necessarily true in humans. "The immune system of a mouse is a parallel universe to the immune system of higher primates," said Randall Morris, MD, professor of cardiothoracic surgery and Hausen's collaborator on the study. Looking for an alternative, Hausen, Morris and colleagues tested the antibodies and two kinds of immune-suppressing drugs in cynomolgus monkeys, whose immune system is more like our own. Twelve monkeys that had undergone kidney transplants received one of three treatments for eight weeks: antibodies alone; antibodies and the immunosuppressant cyclosporine; antibodies and steroids, which also inhibit the immune system. After another eight weeks had passed, the researchers determined whether the monkeys showed signs of organ rejection.

Contrary to conventional wisdom derived from mouse studes, cyclosporine did not interfere with antibody treatment, the team discovered. In fact, the combination of antibodies and cyclosporine was superior to the other two treatments used alone, Hausen told the American Society for Transplantation's annual meeting in Chicago on May 14. All eight of the monkeys treated with antibodies alone or the steroid-antibody combination showed signs of organ rejection. But only one of the four treated with cyclosporine and antibodies developed rejection.

To the researchers' surprise, the antibodies alone did not induce tolerance, as they had done without fail in mice. "The mouse data were so persuasive that these monoclonals could produce tolerance," Morris said. "I thought this was the solution ­ I really believed it. But I have been misled by results in mice many times before."

What the results suggest, Hausen said, is that clinical trials of monoclonal antibodies as an adjunct to approved immunosuppressants like cyclosporine are now feasible. "We could use monoclonals to reduce the amount of toxic drugs without increasing the risk of rejection," he said.

Additional Stanford collaborators on the project were postdoctoral fellow Jochen Klupp, MD, and technician Laurie Hook. The remaining collaborators were Roxanne Baumgartner, MD, of The Naval Medical Research Center in Bethesda, Md; Uwe Christians, MD, PhD, of the University of California, San Francisco; and Stuart Friedrich, PhD, and Abbie Celnicker, PhD, of the Genetics Institute. SR