Study May Show How Fetus Protects Itself in Womb

Researchers may have solved the enduring mystery of how a fetus is able to evade its mother’s immune system for the nine months of pregnancy--a discovery that could lead to new drugs to prevent transplant rejection, to help women who have difficulty conceiving and even to safely induce abortions.

Normally, the human immune system reacts against any foreign tissue in the body and tries to destroy it. And because half of an infant’s genes come from the father, “we are transplants for the nine months of our lives before we ever come out into the world,” said Dr. Andrew L. Mellor, who led the research.

“Our discovery addresses the paradox of how mammals, including human beings, survive in the potentially hostile environment of the womb.”

Scientists have long believed that the developing fetus avoids destruction because the mother has a protective mechanism that somehow creates a “privileged” site--the womb--where rejection doesn’t occur.

The new research indicates it is the fetus that creates a privileged site. It does so by mounting a guerrilla operation against the mother’s immune cells by secreting an enzyme that blocks a key component of the immune response.

Inadequate production by the fetal cells of the enzyme, indoleamine 2,3-dioxygenase, known as IDO, may play a key role in spontaneous miscarriages, according to the research that the team from the Medical College of Georgia reports today in the journal Science.

If that can be demonstrated, Mellor said, it may well be possible to develop drugs that mimic the action of IDO or stimulate increased production of the enzyme.

Alternatively, it might be possible to administer IDO inhibitors to provoke a miscarriage when an abortion is desired.

Interfering with tryptophan metabolism to protect a transplant may be more difficult because the amino acid is required throughout the body. But when researchers learn how the lack of tryptophan results in tolerance, they will almost certainly identify a biological pathway that can be attacked at other points.

“That’s probably where the real opportunity would exist for clinical application,” said Dr. Robertson Parkman of USC, who called the results “provocative.”

The task now, Parkman said, is to completely understand the biological pathway involved in the hope of finding specific places to interfere with it to protect transplanted organs.

The immunological paradox of fetal survival was formulated about 55 years ago by immunologist Peter B. Medawar, who discovered the immunological mechanism that explains why foreign tissues are rejected by the body.

Medawar had speculated that the fetus might be physically separated from the mother by the placenta, that it might not develop immune-provoking tissues until after birth, or that the mother has some mechanism to suppress the rejection.

The first two speculated mechanisms have long since been rejected. Scientists now know, for example, that the placenta does not prevent cells from the mother’s immune system from reaching the fetus.

The catalyst for the new discovery was test-tube work by Dr. David H. Munn, who was investigating how white blood cells called macrophages can block the ability of T cells, another form of white blood cell, to attack foreign tissues.

About a year ago, he discovered that the macrophages worked by destroying an amino acid called tryptophan that T cells must have to initiate their attack. The macrophages, he said, are like little black holes that suck all the tryptophan out of the nutrient solution.

The destruction of tryptophan was accomplished by IDO.

It was already known that fetus-derived cells in the placenta secrete IDO, although the enzyme’s purpose was not clear. Munn and Mellor speculated that IDO’s role was to block the mother’s immune attack, and set about trying to prove it.

In the key experiment, they used two groups of pregnant mice. In the first group, the females were impregnated by highly inbred males that were virtually identical genetically to the females. In the second group, the males were from a different strain.

The researchers then implanted in the pregnant females time-release capsules containing either a potent inhibitor of IDO or a placebo. All the mice given a placebo delivered normally.

The inbred mice given the IDO inhibitor also delivered normally. But the mice bearing the “foreign” fetuses suffered miscarriages.

“It was absolutely dramatic,” Mellor said. “Every single fetus got rejected.”

Other experiments supported the conclusion that destruction of tryptophan was the key to blocking rejection.