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NEW TRANSPLANT DRUG WORKS IN MONKEYS
STANFORD -- An experimental drug delays organ rejection in rhesus monkeys with transplanted hearts, researchers from Stanford University Medical Center and Genentech Inc. have announced.
The drug, anti-LFA-1, may be useful both for ensuring proper functioning of organs soon after transplantation and for preventing long-term rejection, said Dr. Randall Morris, professor and director of transplantation immunology in the Department of Cardiothoracic Surgery at Stanford.
The drug works by preventing the immune system's T cells from attacking graft tissues. It does this in two ways, Morris said. Anti-LFA-1 stops the T cells from sticking to foreign tissue, making it more difficult for them to damage newly transplanted organs. It also reduces the proliferation of T cells that eventually causes rejection of transplants.
Anti-LFA-1 appears to be nontoxic -- a feature that would make it an ideal addition to current transplantation drug regimens, Morris noted. With an effective, nontoxic drug available, physicians could use other drugs in lower amounts, thereby reducing or eliminating the significant side effects that plague transplant recipients taking the existing drugs.
The monkey trial follows up on the first successful mouse trial with this drug, conducted by Morris several years ago. Stanford postdoctoral fellow Dr. Robert Poston will present the new results on Sunday, May 11, at the American Society for Transplant Physicians' meeting in Chicago.
Morris and Dr. Robert Robbins, assistant professor of cardiothoracic surgery at Stanford, contributed to the new study, as did Elizabeth Chan, Paul Sims and Paula Jardieu of Genentech Inc., a biotechnology firm based in South San Francisco.
The researchers tested anti-LFA-1 on five monkeys receiving heart transplants, while five other monkeys received transplants but no drug treatment. The untreated group survived an average of eight days, whereas the treated group survived an average of 23 days. Far longer response times are expected in humans because the drug was designed for use in humans and not monkeys, Morris said.
Anti-LFA-1 is an antibody that specifically recognizes a protein on the outside of T cells. By attaching itself to this protein, the drug stops the protein from doing its job. The protein, called LFA-1, normally helps T cells stick to cells recognized as foreign or damaged. The T cells can then encourage other immune-system cells to attack and destroy the unwanted cells.
The sticking of T cells to foreign tissue is a particular problem in the early stages of a transplant, said Morris. Organs destined for transplantation are kept cold to minimize any damage from the temporary absence of an oxygen-rich blood supply, but the organs still respond to the lack of oxygen as if they were damaged: They make more sticky proteins so that immune cells can be recruited to clear away any damaged cells. The immune response by the organ recipient is, however, over eager, and the recipient's recruited cells cause more damage.
"You have a vicious cycle of increased injury and sticking," Morris said. "But if you can decrease sticking, you can reduce graft damage."
A drug that reduces this kind of graft damage would be especially critical for the 20 to 30 percent of kidney transplant patients whose grafts do not work immediately because of early damage responses, he said.
Once a graft is established, the immune system recognizes it as foreign. The LFA-1 protein is also important in this recognition process. Whenever LFA-1 detects the sticking of a T cell to a foreign cell, it sends a signal into the T cell that causes the T cell to reproduce itself.
"This proliferation is a prelude to rejection," Morris explained. Once there are enough T cells that recognize the graft as foreign, they can overwhelm the graft and cause rejection.
But anti-LFA-1 prevents the signaling that initiates this, he said, so the number of T cells stays low.
Anti-LFA-1 differs from OKT3 -- the only antibody today used clinically for transplantation-- in that it does not deplete the body's supply of T cells. This is an advantage, said Morris, since "severe depletion predisposes to infection and cancer." OKT3 also causes T cells to release molecular messengers normally used to indicate infection by viruses, so patients who take OKT3 suffer the debilitating symptoms of a viral infection. The Stanford team detected no such response to anti-LFA-1 in the monkeys, Morris said.
To develop the new drug, the researchers used classical immunology followed by biotechnology. First, they isolated the antibody from mice exposed to human LFA-1. Other researchers had used a similar antibody in earlier clinical trials, but the human immune system recognized the mouse antibody as foreign and swiftly rejected it. To develop a drug that is useful in the long term, the Genentech scientists replaced all but a few critical portions of the mouse antibody with the equivalent portions of a human antibody.
The few mouse sections left are enough for the antibody to recognize LFA-1 but should not be sufficient for recognition and rejection by the human immune system, Morris said. The human portions are, however, recognized as foreign by the monkeys, causing the monkeys' immune systems to neutralize the drug. This limited the treatment's effective lifetime in monkeys to less than a month.
The human immune system will not reject this human protein, so the drug should last far longer and infrequent doses may suffice, Morris said.
The success of anti-LFA-1 in the monkey trials has encouraged the researchers to plan human trials, he added. Morris said he expects that physicians will eventually use anti-LFA-1 in combination with the existing transplant drugs, such as cyclosporine, steroids and azathioprine. ###
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