Innate immunity may be the key to organ rejection

By Byron Spice, Pittsburgh Post-Gazette

January 25, 2006

In the decades since surgeons began transplanting organs, the problem has remained the same: How do you keep the patient's immune system from attacking and killing the new organ?

Immunosuppression drugs can keep organ rejection at bay, even as they cause undesirable side effects, but reliable methods for inducing a patient's body to accept a new organ have proven elusive.

Dr. Fadi Lakkis, the new scientific director for the University of Pittsburgh's Starzl Transplantation Institute, suspects that the insights into curbing rejection that he and his colleagues have been seeking are buried in hundreds of millions of years of evolution.

In particular, he thinks they may be embodied by hydractinia, a relative of coral and jellyfish. The creature is so primitive that it has no heart, no liver, no kidneys. Its differences with humans don't stop there; it reproduces both sexually and asexually, can grow by fusing with others and, theoretically, could live forever.

"We're basically down at the base of the animal kingdom" said Dr. Lakkis, a nephrologist who joined Pitt last fall from Yale University.

But hydractinia, which evolved 650 million years ago, can tell the difference between relatives and non-relatives and have a way of fighting non-relatives that looks remarkably similar to what occurs in organ rejection in humans.

Observing hydractinia, which can be readily grown on a microscope slide, gives researchers an unobstructed view of what is called the innate immune system, he explained. Over the past decade or so, transplant researchers have begun to suspect that this inherited system, which has been conserved through evolution and remains a component of the complex human immune system, plays a key role in rejection.

Much of the attention of transplant researchers up until now has focused on the adaptive immune system -- the T cells, B cells and antibodies that can mount a highly selective and effective campaign against foreign invaders. Most anti-rejection drugs, such as cyclosporine and tacrolimus, act against the adaptive system.

"You can think of the innate immune system as a giant doorbell," Dr. Lakkis said. Components of the innate system -- macrophages, natural killer cells and proteins known as complement -- can mount their own attack against invaders, but also serve to alert the more sophisticated adaptive immune system.

Components of the innate system can mount a rapid and devastating form of rejection, called hyperacute rejection, but that generally occurs when there is a large mismatch between tissues, such as occurs when transplants occur between species.

But Dr. Scott M. Palmer, a pulmonologist who is medical director of the lung transplant program at Duke University Medical Center, said many researchers now believe that the innate immune system's more subtle role as a detector for the adaptive system may be key to organ rejection.

"That initial response may program the rest of the immune response," he said.

The innate immune system, he added, "is a relatively new idea in immunology and an even newer idea in terms of it having something to do with transplants." It was little more than 15 years ago that the late Dr. Charles A. Janeway, a Yale immunologist, proposed the concept of the innate immune system.

Why does rejection occur?

It may go a long way toward explaining why organ rejection is a problem at all. It isn't surprising, for instance, that animals would evolve an immune system to protect against such common threats as bacteria and viruses, said Leo Buss, an evolutionary biologist at Yale. But why would animals evolve such a strong defense against surgically transplanted tissue?

"It doesn't make much evolutionary sense," Dr. Buss said. "It's well-adapted to an event that is never going to occur" in nature.

If the life cycle of hydractinia is a guide, that strong reaction against non-related tissues has to do with an animal's evolutionary impulse to protect its genetic identity.

Hydractinia reproduce sexually, producing a free-swimming larva that metamorphoses into a polyp -- a tube-like body with a mouth on one end. The polyp attaches to a surface; in Long Island Sound, that surface is preferentially the shell of a hermit crab. It grows as a mat against the shell and can produce additional polyps asexually.

This hydractinia colony also can grow by fusing with other hydractinia it encounters on the surface, said Dr. Buss, who has been studying the animal for a quarter century. But because it wants to advance its own germline, colonies will only fuse with relatives; even then, there is competition within the newly fused colonies to determine what individuals will produce the colony's reproductive cells.

When two non-relatives bump into each other, they launch into a fight to the death, shooting coiled, toxic harpoons called nemacysts at each other until one succumbs.

Microscopically, this reaction appears similar to organ rejection, producing areas of necrotic tissue between the hydractinia, Dr. Lakkis said.

Evolutionary wisdom

This ability to differentiate between self and non-self makes sense in hydractinia, but that doesn't explain why this ability has been preserved through evolution and continues to be found in humans.

"Why do we need it? We don't fuse," Dr. Lakkis said. But it may well prove important in pregnant women. As fetal stem cells enter the mother's circulation, this mechanism may be at work; no one knows for sure, he said, but the mother may reject the fetal stem cells. That also has implications for potential stem cell therapies.

A similar rejection phenomenon occurs between sponges, an even more primitive creature that evolved 800 million years ago, said Dr. Lakkis, who became interested in immunology as a medical student at American University of Beruit.

Because they don't have adaptive immune systems, these simple creatures make it easier to study the innate system, explained Dr. Lakkis, who as a nephrologist treats kidney transplant recipients. He initially tried to use the sponges for his research, but found that they were too hard to grow in the lab.

A student at Yale first alerted Dr. Lakkis to the work of Dr. Buss, who had shown that hydractinia could be grown readily in the lab. Thus began a collaboration between them and a third Yale researcher, plant geneticist Stephen Dellaporta.

After what Dr. Buss describes as a long slog, the researchers have identified a piece of the hydractinia chromosome that contains the genes responsible for the innate immune response and should soon be able to identify all of the relevant genes. "We're maybe three months away," he added.

Just how this knowledge will be translated into clinical medicine remains to be seen. At this point, noted Duke's Dr. Palmer, researchers don't have the tools for inhibiting the innate immune system in the same way they can use cyclosporine or tacrolimus to inhibit the adaptive system.

And just as inhibiting the adaptive system can have negative side effects -- more infections, cancers -- inhibiting the innate system is likely to cause problems not yet recognized, he added.

It remains an open question whether tolerance can be induced in hydractinia. A method that works in mice -- combining two embryos to create an intermingling of cell types called chimerism -- has been a bust in hydractinia, said Dr. Lakkis, who will soon move his own hydractinia colonies to his lab in Pitt's Biomedical Science Tower 3.

"It is really making us rethink transplantation," he said.

(Post-Gazette science editor Byron Spice can be reached at bspice@post-gazette.com or 412-263-1578.)

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This article posted February 19, 2006.