Altered Antibody Boosts Transplants

(Edited for publication--R.S.)

The immune system takes a dim view of transplants. Any tissue or blood that doesn't come from an identical twin counts as  foreign matter to be destroyed. Treatment with immune-suppressing drugs can counteract such rejection, but it leaves the individual vulnerable to cancer or other ills. Even with drug treatment, many patients reject transplants.

At the core of this reaction is a molecule called CD154. It signals T cells--the immune system's shock troops--to spring into action against transplants. Two studies in rhesus monkeys now show that a drug called hu5C8 can waylay this attack without shutting down the rest of the immune system. The antibody binds to CD154, blocking the chain reaction that would have led to overzealous manufacture of T cells.

In a study described in the June NATURE MEDICINE, scientists gave nine rhesus monkeys kidney  transplants from unrelated donors and also intravenous doses of hu5C8 which is made by Biogen in Cambridge, Mass. Previous studies showed that this genetically engineered version of a human antibody might block T cell activation (SN: 8/9/97, p. 84).

One of the nine treated monkeys died of unrelated causes, but the other eight are thriving with their transpanted kidneys. Five of these animals completed their 5-month regime of antibody treatment about a year ago, says study coaththor Dr. Allan D. Kirk, a transplant surgeon at the Naval Medical Research Center in Bethesda, Md.

Four other monkeys, which received a transplant but not the antibody, rejected the transplanted kidneys within 8 days. Eleven monkeys getting a combination of the antibody and standard immune-suppressing drugs showed mixed results--some rejected the organs, others didn't.

In a separate study, researchers removed the pancreases of six rhesus monkeys and then gave them hu5C8 along with new pancreatic islet cells from unrelated donors. The transplanted cells, placed in the monkeys' livers, weren't rejected, says study coauthor Norma S. Kenyon, a transplant immunologist at the University of Miami School of Medicine. Two monkeys that didn't receive the antibody rejected islet cells.

This study, to be published this summer in the PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, raises hopes for diabetes patients. Islet cells normally make the hormone insulin, and the transplanted cells started producing it immediately. The experiment suggests a means to reverse type 1, or juvenile-onset, diabetes, a condition in which islet cells are destroyed. "I don't want to raise false hopes, but I think this is a very big step forward," Kenyon says.

ln a study of baboons to be published soon in DIABETES, Kenyon and her colleagues show that hu5C8 also reversed rejection in four baboons that had earlier received islet cell transplants.

"This is an exciting drug," says Mitchell L. Henry, a surgeon at Ohio State University in Columbus. He's impressed that two types of organ transplants succeeded.

In all these experiments, the antibody's precise role remains a mystery.

"Our immune system didn't evolve [just] to keep us from getting transplants. It is aimed at infectious pathogens," says endocrinologist David M. Harlan of the Naval Medical Research Center in Bethesda, Md., who participated in all three studies, as did Kirk. Transplant rejection may simply be a case of mistaken identity, and CD154 may somehow remedy the problem.

Evolution may have provided compounds that act as shutoff switches each time T cells are produced to mount an attack, Harlan suggests. The antibody hu5C8 may somehow tap into that mechanism, he says.

This model could explain why suppression drugs hampered hu5C8's effectiveness in the kidney-transplant experiment. The drugs could be keeping T cells from processing a shutoff signal, Kirk says.

"The lesson is that we must choose our signals carefully, not simply block them all," says Polly Matzinger of the National Institute of Allergy and Infectious Diseases in Bethesda. Md., writing in NATURE  MEDICINE.

--N. Seppa

NOTE: Reprinted without permission from Science News, Vol. 155, June 12, 1999. If any copyrights are infringed, please notify me and I will remove it immediately. Roger Stevens.

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