A hormone known for its involvement in the brain's response to stress also plays a key role in shielding the developing embryo from its mother's immune system. In its newly identified function, corticotropin-releasing hormone (CRF) stimulates the production of a protein previously found to prevent maternal immune cells from attacking embryonic tissue.
The immune system is primed to reject any cells, even those of an embryo, that display an immune chemistry distinct from their host's. Yet in most pregnant women, embryos are spared by a poorly understood mechanism that holds her immune cells at bay.
Earlier research suggested that the interaction between proteins called Fas and Fas ligand (FasL) keeps potentially dangerous maternal immune cells safely away from the embryo (SN: 6/14/97, p. 371). Fas resides on the surface of immune cells called T cells. FasL is produced in embryonic cells called trophoblasts, which encase the developing embryo. By binding to Fas molecules on T cells approaching the embryo, FasL prompts these cells to undergo cell suicide, or apoptosis.
In the new study, researchers led by Antonis Makrigiannakis of the University of Crete in Greece examined human trophoblast cells isolated in tissue cultures. They found that these embryonic cells produce CRH. The cells also display surface receptors that bind to CRH and so probably respond to their own hormones.
When the researchers added extra CRH to some of the cultures, they observed an increase in the amount of FasL produced. The hormone had the same effect on cells from the lining of a woman's uterus, the researchers report in the October NATURE IMMUNOLOGY.
The researchers then introduced T cells bearing Fas into the cultures to see whether the FasL produced would head off an immune attack. In cultures augmented by additional CRH, nearly 70 percent of the T cells committed suicide. In contrast, in the other cultures, only 15 percent of T cells died through apoptosis. T cells without Fas, which don't attack foreign tissue, didn't suffer apoptosis under either condition.
The researchers conclude that CRH triggers embryonic cells and nearby uterine tissue to express FasL, which destroys threatening T cells.
In a separate set of experiments, the researchers injected pregnant rats with antalarmin, a molecule that blocks CRH from docking on cells and triggering FasL production. Fewer embryos attached successfully to the uterus in rats receiving antalarmin than in control rats. When embryos did attach, the implantation site produced less FasL than usual.
Antalarmin received on or after the ninth day of the rats' 3-week gestation period, however, didn't disrupt pregnancies. This suggests that the CRH-FasL relationship plays its anti-immune role only in very early pregnancy, say the researchers.
The new study "provides a role for CRH in maternal immune tolerance that's never been described before," says Scott W. Kauma, a reproductive immunologist at Virginia Commonwealth University in Richmond. "It confirms the importance of Fas ligand" and identifies a control factor for the molecule's production in trophoblasts, he adds.
The possibility of manipulating a woman's immune response with antalarmin could lead to new methods for ending early pregnancies, says Makrigiannakis' team.
Antalarmin might not be safe used in this way, however, unless it could be applied locally, points out Joan S. Hunt, a reproductive immunologist at the University of Kansas Medical Center in Kansas City. CRH has many effects throughout the body.
It's conceivable that CRH could be administered to treat certain types of infertility, Hunt says. But, again, its effects outside of pregnancy would need to be considered. Hunt suggests that future research might examine how certain mice that lack CRH receptors nevertheless manage to reproduce.
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