By David N. Leff

Science Editor

When a cluster of foreign cells begins to proliferate into a swelling mass inside a woman's abdomen, how can her immune system tell the difference between a cancer and an embryo? Scientists and clinicians invoke this long-unanswered question as a mystery, a puzzle, an enigma.

Those alien antigens, of course, come from the male parent's spermatic contribution to reproduction; it seemingly should be ripe for immune rejection. Molecular endocrinologist Bert O'Malley suggests that progesterone, the master hormone of mammalian reproduction, guards the gates of fetal gestation against any misguided attack by cytotoxic T cells of the immune system.

He backs up that suggestion with evidence reported in the current Proceedings of the National Academy of Sciences (PNAS), dated Oct. 12, 1999. O'Malley, chairman of molecular and cellular biology at Baylor College of Medicine in Houston, is senior author of the paper, which bears the title: "Progesterone receptors in the thymus are required for thymic involution during pregnancy and for normal fertility."

"In a sense," O'Malley told BioWorld Today, "the fetus is immune-privileged. Of course it's not attacked like a foreign antigen, as all other foreign things in the body are. So it can grow into an individual."

Some years ago, by targeted gene deletion, he and his co-authors generated a strain of PRKO knockout mice that lacked the gene for making the progesterone receptor (PR). "One of the things we noted," he recalled, "was that evolutionarily everything involving reproduction seemed to have evolved under control of this receptor."

O'Malley counted the ways: "PR starts with things as diverse as some aspects of pheromone function. It has a regulatory role in sexual behavior in both males and females. It is involved in causing the release of an egg from the ovary, that could be fertilizable by sperm. After that," O'Malley continued, "PR prepares the uterus for implantation of the fertilized egg. And finally, after delivery of the infant, progesterone receptors prepare the mammary ducts and glands to give milk. In other words, PR governs the entire reproduction package."

Murine Foreplay Gets Ball Rolling

In fact, O'Malley related, "It's a response in the female mouse that is part of the reproductive act in mice. When a male approaches a female for copulation, if the female is not interested, she will kick the male off. However, if the hormonal state is right, when the male touches the flanks of the female, she splays her legs out, puts her tail to one side so he may enter, and arches her back. She has an almost reflex orgasmic, shivering action when the male copulates, which we can quantify."

As his PNAS article indicates, the progesterone receptor tells only half the story of why the growing fetus enjoys immune tolerance from rejection. "The T cells are made by the bone marrow. They pass through the thymus and mature there," he explained, "after which they can come out as active immune fighter cells. So if the thymus regressed, you would lose a reservoir of many of these cells.

"Normally," he added, "in mice and humans, too, the thymus regresses tremendously during pregnancy. It shrivels to a very small size, losing 90 to 95 percent of its mass. Then, six to seven weeks after pregnancy's over, it all comes back again to its normal size. This much was known."

So O'Malley and his co-authors asked: "Why would that thymal shrinkage occur if it wasn't maybe required for pregnancy? We noticed that in the progesterone receptor KO mouse the thymus didn't regress at all, or hardly at all. So we figured that if the regression occurred during pregnancy, and it's also under control of the progesterone receptor, then that may be part and parcel of this combined set of factors required for fertilization and delivery of the fetus."

In a final in vivo experiment, they removed the thymus from normal and KO mice, and transplanted them. "The bottom line," O'Malley recounted, "is that the thymus from the normal animals seemed to work fine in the PRKO mice. They got pregnant and delivered healthy fetuses. Whereas, if we implanted the PRKO mouse thymus into normal wild-type animals, they had a greatly decreased fertility, with fetal loss and fewer viable pups."

He made the point, "This result didn't show that it was an all-or-nothing phenomenon on the thymus. Other immune system factors are also in play. But it did show, I think for the first time, that the thymus does play a significant role in pregnancy. And it's only because that experiment couldn't be done before - because the PRKO mouse didn't exist - that we were able to demonstrate this effect.

Do these results solve that sweet mystery of life once and for all?

"First of all," O'Malley pointed out, "this is perhaps one of the larger - some people say the greatest - mystery in reproduction, other than how the whole complicated process itself works. Why the immune system, which attacks every little molecule that's different from self, would allow this growing fetus in there, and not just have the immune system go after it."

Potential Diagnostics, Enhancers, Contraceptives

"I think our findings are definitely a major part of the fetal immune tolerance, and therefore it's quite likely that this is a pathway that would be defective in some human subpopulation - the 10 percent or so of women who have fertility problems - are less fertile, or lose their pregnancies, or don't implant well, have spontaneous abortions early, or fail to get pregnant," he said. "I think this is something that will be considered in the future by people in OB/GYN or other fields where they're looking directly into the genetics of some defect in this thymus regression.

"That's a diagnostic potential for infertility clinics," O'Malley suggested. "Perhaps bioscan the thymus, take a picture, guess its weight, see if it regresses well in pregnancy. Eventually one might be able to provide some drug that would enhance thymus regression for those with pregnancy maintenance problems. Or perhaps do something else in the immune system that thymus regression is doing, and thereby enhance fertility." Changing gears, he added: "And if you could block thymus regression, you might consider the contraceptive side of things, but I think that's probably less likely then enhancing the fertility."