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When the National Institutes of Health requested proposals for innovative ideas in immune system suppression from scientists who aren't immunologists, Dr. Vadivel Ganapathy, biochemist, and his idea qualified.
The Medical College of Georgia researcher 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 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.
Progesterone is a female hormone with receptors found throughout the body; physicians and scientists have long known progesterone and estrogen are needed in pregnancy. It's also known that during pregnancy, the placenta produces a tremendous amount of progesterone, hundreds times more than needed to activate progesterone receptors. Scientists also have known, at least since the 1977 article, that at these high levels, progesterone kills lymphocytes, white blood cells critical to the immune response.
Dr. Ganapathy began to put together an answer to the nearly 30-year-old question when he was looking at the impact of cocaine on the fetus and found a placental protein called sigma receptor interacts with cocaine. In 1996, he cloned the sigma receptor from human placental tissue so he could complete a biochemical profile on exactly how it worked. By then, other scientists had speculated that the ligand or activator of this receptor was progesterone. "We thought, ‘We can establish that without any doubt by using our cloned receptor,'" Dr. Ganapathy said. "So instead of taking tissue and looking at the progesterone binding to it, we can look at the cloned, pure protein receptor and show that progesterone is the ligand. We published that."
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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.
So he is developing a knockout mouse model that is missing the sigma receptor to see if the mice ever get pregnant. He's betting they won't.
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.
But there may be even more, possibly another ligand or activator for the sigma receptor that would enable use of this process to locally suppress the immune system so organ transplant patients wouldn't need drugs that more generally suppress, leaving them susceptible to illness and infection. Dr. Ganapathy said a French company is trying to synthesize such ligands.
"It's a nice theory," he said; finally he may find if it's a reality.