By Dean Haycock

Special To BioWorld Today

Expectant mothers may not see their unborn children as foreign bodies, but immunologists often do. Half of the fetus's genes, after all, come from a third party, the father. Why doesn't the mother's immune system attack the fetus the way it would a transplanted heart?

That question has stumped immunologists for years.

The fetus is separated from the rest of the mother's body by a placental barrier. Many substances can pass through the barrier - water, salt, nutrients, hormones, even some drugs and viruses - but not the mother's blood cells. This physical separation, however, cannot account for the fetus's privileged status. The placenta itself is a product of the same fertilization process that fused the hereditary material of the mother and father. It too is "non-self" as far as the mother's immune system is concerned. It too should be destroyed.

In recent years, the search for an explanation of this vintage conundrum has settled on the possibility that the mother's immune system is somehow induced to "look the other way," to develop an immunologic tolerance or "inertness" toward the fetus.

A paper in the Aug. 21 issue of Science, "Prevention of Allogeneic Fetal Rejection by Tryptophan Catabolism," provides intriguing data in support of this possibility. The paper offers a specific mechanism by which the fetus may survive what would otherwise be a hostile environment. Andrew Mellor, professor of medicine at the Medical College of Georgia, in Augusta, and his co-authors suggest that the cells in the placenta produce a substance that robs immune cells of an essential nutrient, the amino acid tryptophan. Without it, host T cells cannot proliferate and attack.

The placental secret weapon, according to the scenario offered by the authors, is an enzyme called indoleamine 2,3-dioxygenase (IDO).

The work originated with the unexpected observation by co-author David Munn of the Medical College of Georgia and his co-workers that immune cells called macrophages seemed to suppress the activation of T cells in cell cultures. The macrophages appeared to be depriving T cells of tryptophan, an essential amino acid that must be supplied in the diet since humans cannot synthesize it.

It turned out that the macrophages produced IDO, the same tryptophan-destroying enzyme that had been shown years earlier to be produced by cells in the placenta. Perhaps, the researchers reasoned, placental cells prevent the mother's T cells from attacking by depriving them of tryptophan.

To test their hypothesis, the researchers determined the effects of IDO inhibition on pregnant mice that were carrying fetuses fathered by genetically identical males of the same inbred strain. These fetuses did not appear foreign to the mother. For comparison, they also tested the effects of IDO inhibition on fetuses whose fathers and mothers were of unrelated strains.

The scientists administered to both groups an IDO inhibitor called 1-methyl-tryptophan. Inhibition of IDO in the mice made pregnant by genetically identical fathers did not affect development of the fetuses. Only mice made pregnant by unrelated males were affected by the IDO inhibitor. Their fetuses were lost after the mother's immune system attacked the placenta. The result suggests that in these mice, IDO, before it was inhibited, was preventing immune cells from destroying the placenta and the gestating mice.

'Sensing' Mechanism Suspected

Experiments with transgenic and other strains of mice suggest that the immune cells responsible for attacking the placenta are T cells.

"We think that cells that catabolize tryptophan - [that] remove tryptophan from their immediate environment - somehow stop T cells that would like to respond from responding," Mellor told BioWorld Today.

How that happens is still subject to question.

"It is very difficult to work on (that question) in the context of the whole organism, of course, so we are trying to model the situation in vitro." Mellor said.

A simplistic explanation would be that depriving T cells of tryptophan would prevent them from synthesizing proteins of which tryptophan is one building block. Recent in vitro experiments suggest that it is not that simple.

"Our current working hypothesis is that there must be a more sophisticated 'sensing' mechanism by which the tryptophan concentration in which the T cells are attempting to grow is somehow monitored," Mellor said. This would allow or prevent T cells from entering their growth cycle, which they must do to defend the body.

"This mechanism of nutrient depletion is generally regarded as a rather blunt way of dealing with the situation of controlling cell proliferation," Mellor said. "And nobody for a moment, I think, suspected the sophisticated process of protecting the mammalian fetus from attack by the mother's immune system would actually come down to this level."

More work must be done to strengthen the theory that the fetus is protected from the mother's immune system by release of IDO from placental cells. Ongoing experiments, however, suggest that this mechanism may be in place in healthy tissue elsewhere in the body. In this case, macrophages are the prime suspects for keeping T cells under control. The integrity of this system could determine whether a person will get an autoimmune disease.

The researchers quickly realized that they had made a patentable discovery. The Medical College of Georgia has filed four patents as a result.

Talk with venture capitalists followed, but the researchers for now are concentrating on gaining patents as they generate more data.

Their work has been funded by the Medical College of Georgia, the Mason Trust in Atlanta (a charitable organization), and grants from the National Institutes of Health. *