By David Leff

BOSTON - Organ transplantation has become the surgical success story of the past four decades, but it has its down sides. For one thing, the recipient of a donor kidney, heart, lung or liver - unless the donation comes from an identical twin - faces a lifetime on nonspecific immunosuppressant drugs.

That pitiless regimen may save his or her organ by warding off graft rejection, but that Faustian bargain is at the cost of being perpetually naked to agents of infection, whether bacteria, viruses, fungi, whatever. An incidental burden is the recipient's round "moonface" - badge of chronic immunosuppression.

If, instead of a new solid organ, the transplant consists of treating leukemia or lymphoma by inserting bone marrow cells - ideally donated by a brother or sister to minimize the mismatched antigens, which the recipient's blood unleashes against the foreign intruder. This may involve another serious clinical tax levied against the recipient patient - wiping all his immune cells out of his bone marrow to deny the incoming donor cells a target for rejection. This cellular cleansing takes the form of whole-body ionizing radiation, which itself has horrendous side effects, not to mention lethal risks.

So transplant immunologists chase after at least three holy grails:

¿ Side-stepping whole-body radiation.

¿ Limiting immunosuppression to a short treatment, rather than a life sentence.

¿ Conditioning the recipient's immune system to tolerate rather than reject the gift tissue.

Two transplant immunologists can report progress, not only in mice, monkeys and pigs, but prospectively with human patients.

David Sachs, of Harvard-affiliated Massachusetts General Hospital, and Joseph Davie, senior vice president of research at Biogen in Cambridge, Mass. took part Monday morning in the first Science Symposium of BIO 2000, on the theme, "Putting the Immune System to Work: Understanding Control Points in Immune Reactivity."

"Induction of specific transplantation tolerance," Sachs said, "is based on mixed chimerism. "It's been known for many years," he noted, "that you can get complete tolerance to any tissue from a donor if you can get a bone marrow transplant to take. This is known not only from animal models, but clinical examples. There are patients who have had a bone marrow transplant for leukemia from an immunologically identical sibling, then years later developed kidney failure from unrelated causes. And it required a kidney transplant.

"In some cases," Sachs added, "those patients have remained on sufficiently good terms with the original sibling that they've received a kidney from that same donor, And in all of those cases, the kidney has taken without requiring immunosuppression. Tolerance goes along with the taking of that bone marrow transplant.

"Those cases were all identical siblings," Sachs said, "And there are some cases in leukemia where you want to ablate the host completely and replace the recipient bone marrow with that of the donor. In order to induce that tolerance, you don't need to replace the entire amount. All you need to do is get the right amount of the right cells of the marrow to take at the right place. You don't have to worry about mismatches or compatibility of the immune system."

Moving from mice to primates, Sachs successfully applied his mixed chimera tolerance induction to cynomolgus monkeys. The trouble with these close-to-human animals, he pointed out, is their size. No cynomolgus kidneys or hearts would fit in a human patient's body. Therefore, he and his colleagues are turning to "mini-swine," which weigh in at 200 to 300 pounds - which is in the human physical ballpark.

"So pigs are the xenotransplant donors of choice," he said. So far, his group has supported a host monkey short-term with a donor porcine kidney transplant.

Biogen's Joseph Davie reported "very interesting results in kidney transplants. Treatment with [Biogen's proprietary] anti-CD40 ligand antibodies was sufficient to maintain kidney allografts in mice for a very long period of time. We could stop administering the drug after something on the order of six months treatment, and continue to maintain that graft.

"Long after the drug was gone, Davie said, "the animals' immune system did not become reactivated and reject the kidney graft. We had some mice," he told his audience, "who went longer than a year with no treatment after having received six months' early treatment with anti-CD40 ligand."

This, he said, "is a form of peripheral tolerance. It may very well be the result of the stimulation of apoptosis [programmed cell death] in the T lymphocyte populations. In ways when CD40 is blocked, that results then in killing of T lymphocyte."

Davie explained that "CD40 ligand is a member of the tumor necrosis factor family. It is expressed only on activated T lymphocytes, [the perpetrators of organ rejection] and activated platelets, as best as anybody can tell. And it's present transiently - only for a few days following T cell activation."

He described "the successful completion of a Phase II trial in humans treating ITP - idiopathic thrombocytopenic purpura, which is an autoimmune disease of blood platelets. Patients with ITP have very low platelet levels - sometimes so low that they have bleeding disorders. Because it's thought to be caused by antibodies to platelets, we took patients with moderate to severe ITP and treated them with anti-CD40 ligand.

"That is the molecule that is on the T cell," Davie explained. CD40 without the ligand is on the B cell. The antibody that we use for therapeutics is directed to the T cell. We licensed it from Columbia University in 1993.

He told BioWorld Today that "Biogen has been working on anti-CD40 ligand for several years, and has been interested in applying this to human disease. It has been in man, but is currently back in the research laboratory, trying to determine the cause for certain side effects, particularly thromboses in patients treated with the drug. It is something about which we cannot have any final answers at this juncture, but we're hopeful."

Davie commented to the symposium audience on how his approach and that of MGH's David Sachs differ: "Dr. Sachs has been working for 25 years on human transplantation in kidneys. And he has good data showing how he can create a tolerant situation in interspecies transplants - that is, allografts between two animals, donor and recipient, of the same species. Giving monkey kidneys to monkeys. "With his system, he is able to induce tolerance for kidneys of the same species."

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