Giving the immune system a new start, to prevent transplant rejection

Leveling the immune system might let the body rebuild one that's tolerant of a transplanted kidney. (Photo: Tom Ulrich)

As the science of transplantation has gotten better, the patients whose lives are saved by other people’s organs are living longer and longer. But they’re paying a price—a lifetime of immunosuppressive drugs.  William Harmon, chief of Nephrology at Children’s Hospital Boston, is trying to change that.

After an organ from one person’s body is introduced into another’s, the recipient’s immune system “sees” the new organ as a threat and does what it’s evolved to do when presented with anything foreign: attack it. To protect the new organ and keep it working, recipients must take a strict regimen of drugs, usually several taken two to three times daily. And that’s where the problems begin, especially for children.

Steroids like prednisone tamp down the immune attack on the new organ, but they also can stunt children’s growth and cause weight gain or severe acne. Cyclosporine, another mainstay anti-rejection drug, can cause headache, nausea, tingling fingers and toes, achy joints, unwanted hair growth—girls sometimes develop mustaches—and coarsened facial features. Cyclosporin and tacrolimus, a related transplant drug, can cause kidney damage, a particular problem if it’s a kidney that’s just been transplanted.

All these effects lead many children to resist taking their drugs as they get older, or just become lax, forgetting their medications on the weekends or skipping them when they feel healthy. Statistics show that adolescents have the highest rate of transplant failure of any age group, with kidney transplant patients being among the worst offenders.

About a decade ago, Harmon began looking for other medications for kidney transplant patients that would prevent rejection, but do so with fewer long-term side effects. He began studying Campath, a potent antibody originally used to fight lymphomas that has shown promising results in countering bone marrow transplant rejection. The drug directly targets and destroys a person’s lymphocytes, the same white blood cells that attack transplanted tissues. It then prevents the body from producing new ones – until the new organ is in place.

“We had experience with a few other methods for temporarily eliminating lymphocytes in the past, such as anti-lymphocyte serums, but the results were inconsistent,” Harmon says. “Campath works well on a much more consistent basis. One dose and all the lymphocytes are gone for months.”

There’s a price to pay, of course: The lack of lymphocytes raises the risk of infection, since these cells also fight off infections, so during the months patients receive Campath they also need to take heavy doses of antibiotics.

Slowly but surely, though, the immune system begins to rebound, producing new lymphocytes to replace the ones lost. But here’s the difference: Some of the new lymphocytes, having never known life before the implanted organ, don’t “see” it as foreign, so are less likely to reject it. As immunologists term it, the lymphocytes are “naïve” – they haven’t learned that the organ is foreign.

Campath’s effectiveness and lack of side effects has revolutionized bone marrow transplants and the treatment of pediatric lymphoma. The drug has also been used for small bowel transplant patients who have experienced rejection. But until Harmon’s research, no one had used drug in the treatment of young kidney transplant patients.

Harmon theorized that children would respond well to the drug because of the regenerative nature of their young immune systems. Unlike adults, children have active thymuses – the small organ in the chest where lymphocytes develop.

“We believed going in that children would be more apt to produce naïve lymphocytes after Campath treatment that would be easier for the body to re-educate,” he says.

Harmon’s research (read more about one of his early patients) backs this hypothesis up: Once children are taken off the drug, their immune systems are more accepting of the transplant. As a result, they require less immunosuppressive drugs.

This could reduce the problem of noncompliance with cumbersome regimens and cut the risk of long-term drug-related complications in thousands of children with transplanted organs — potentially saving millions of healthcare dollars.

It’s still early, but Harmon is cautiously optimistic that Campath’s benefits will stand up long-term.

“Everything in the immune system is a balance,” he says. “The question we’re facing now is: If you tinker with it too much, will it affect the body’s natural ability to produce a healthy amount of antibodies later on? We don’t have any evidence that it will, but further study will need to be done to that effect.”

  • Cacotessy

    This is not a new therapy!!!!…and eliminating lymphocytes also put patients at risk!!!!