Is progesterone nature’s immunosuppressant?

The Medical College of Georgia researcher and biochemist, Dr. Vadivel Ganapathy, has spent years studying the placenta and how all sorts of substances, from nutrients to street drugs, are transferred from mother to baby by this two-pound temporary organ of pregnancy.

But he’s long wondered if the placenta, in addition to supplying a developing baby with the nutrition and oxygen he needs to thrive, was also helping suppress the mother’s immune system so the fetus could survive.

“There is the problem about how pregnant mothers tolerate the placenta and the fetus even though the genetic makeup of the placenta is partly different than that of the mother,” Dr. Ganapathy said. “The fetus gets half his genetic makeup from each parent, so when this genetically foreign being implants on the uterine wall he should be rejected — like a transplanted organ — by the mother’s immune system.”

A major research finding in 1998 from another team of MCG researchers led by Drs. Andrew L. Mellor and David Munn (see Tolerance Key to Cancer Survival) showed that early in pregnancy, at the time of implantation, placental cells express an enzyme (indoleamine 2,3-dioxygenase, or IDO) that locally disables the mother’s immune system. “Our IDO mechanism was one that, if you suddenly interrupt it, the fetus can’t do without,” said Dr. Munn, pediatric hematologist-oncologist who also is a co-investigator on Dr. Ganapathy’s study.

Dr. Munn has no doubt that the body has multiple mechanisms to protect the fetus and so procreation. “I think we can state with confidence that the mother and fetus use multiple mechanisms to make sure that the fetus is not rejected,” he said.

Evidence about at least one other mechanism began showing up years ago when an article, published in a 1977 issue of the Annals of the New York Academy of Sciences asked, “Progesterone and Maintenance of Pregnancy: Is Progesterone Nature’s Immunosuppressant?” The question apparently didn’t get answered then, but with the three-year NIH grant Dr. Ganapathy recently secured, it just may.

Now he is exploring the rather common-sense hypothesis that since high-levels of progesterone are needed to activate the sigma receptor in the placenta and that the high levels occur only during pregnancy, this must be one way the placenta helps control the mother’s immune system so the fetus is not rejected.

“It’s a very positive hypothesis, but it’s still a hypothesis,” Dr. Ganapathy said. “There are progesterone receptors in the placenta and in other tissues but to activate them you only need a tiny amount of progesterone. The placenta is producing a ton of it. Therefore the purpose of the placenta-produced progesterone cannot be to activate progesterone receptors,” he said.

The work has potential for not only better understanding the mystery of how the fetus survives but also how the immune system works and, possibly, why sometimes miscarriages occur. “Some women who are infertile may have genetic mutations in the sigma receptors so that progesterone is made by the placenta but the receptor is not functional,” Dr. Ganapathy said.