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Pregnancy Timeline by SemestersFetal liver is producing blood cellsHead may position into pelvisBrain convolutions beginFull TermWhite fat begins to be madeWhite fat begins to be madeHead may position into pelvisImmune system beginningImmune system beginningPeriod of rapid brain growthBrain convolutions beginLungs begin to produce surfactantSensory brain waves begin to activateSensory brain waves begin to activateInner Ear Bones HardenBone marrow starts making blood cellsBone marrow starts making blood cellsBrown fat surrounds lymphatic systemFetal sexual organs visibleFinger and toe prints appearFinger and toe prints appearHeartbeat can be detectedHeartbeat can be detectedBasic Brain Structure in PlaceThe Appearance of SomitesFirst Detectable Brain WavesA Four Chambered HeartBeginning Cerebral HemispheresFemale Reproductive SystemEnd of Embryonic PeriodEnd of Embryonic PeriodFirst Thin Layer of Skin AppearsThird TrimesterSecond TrimesterFirst TrimesterFertilizationDevelopmental Timeline
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Home | Pregnancy Timeline | News Alerts |News Archive Jan 31, 2014

 

Surgery on a fetus to correct a problem such as spina bifida
often results in preterm labor and premature birth - in mice.
Pregnancy complications after fetal surgery trigger activation
of the mother's T cells – the same T cells that cause her body
to reject a donor organ after transplant surgery.






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Fetal surgery and pregnancy complications in mice

A new study provides possible clues as to why a high rate of preterm labor follows human fetal surgery. As a fetal surgeon at University of California San Francisco, Tippi MacKenzie, MD, has long known that conducting surgery on a fetus to correct a problems such as spina bifida often results in preterm labor and premature birth.

Now, MacKenzie and her UCSF colleagues have shown that, in mice at least, pregnancy complications after fetal surgery are triggered by activation of the mother's T cells – the same T cells which cause the body to reject a donor organ after transplant surgery.


"Here at UCSF, the birthplace of fetal surgery, preterm labor has been described as the 'Achilles' heel' of the field because it diminishes the benefit of the surgery itself. However, specific treatments have not been developed because until now, the biological triggers responsible for preterm birth have been unknown."

If the same fetal rejection mechanism is occurring in humans, she said, "we have the ability to design specific medical treatments to prevent it – for example, by using medications that target some of the pathways involved in T cell-mediated rejection."

Tippi MacKenzie, MD, associate professor of surgery, director of research at the UCSF Fetal Treatment Center


The study was published online on January 15, 2014, in the Journal of Immunology in the February 15, 2014 issue.

Normally, pregnancy is a robust form of immune tolerance, in which the pregnant mother naturally tolerates a genetically foreign fetus, MacKenzie explained. "This is in contrast to an organ transplant, where you need to administer immunosuppressive drugs to prevent the body from rejecting a foreign graft. Our study supports the idea that fetal intervention breaks this tolerance by activating the mother's immune system, suggesting that the biology behind preterm labor is similar to transplant rejection."

In their study, MacKenzie and her team used a mouse model of fetal intervention to show that, after fetal surgery, maternal T cells gather in the uterus. According to MacKenzie: "These are effector T cells, which are the main cells responsible for rejecting a transplanted organ. In a shift from the normal balance in the uterus, they outnumber regulatory T cells, which are usually responsible for suppressing an immune response against the fetus."

The scientists next worked with genetically modified mice that had T cells designed to recognize and reject one specific foreign protein. They transferred those T cells into the circulation of pregnant mice whose fetuses expressed that protein because they had inherited the gene from their father. The scientists found in mice that had fetal surgery, the transferred T cells multiplied and migrated to the uterus.


"It's known that in a normal pregnancy T cells that recognize the fetus can circulate in the mother and live in harmony with the fetus. But when you perform fetal surgery, they get activated and rush into the uterus."

Marta Wegorzewska, first author and graduate student in the MacKenzie lab.


Although the activated T cells were an important clue, the researchers' next step was to prove that they had a harmful effect on pregnancy. They designed an experiment in which half of the pups carried by a pregnant mouse were genetically identical to their mother – common among experimental mice – and half were genetically different and expressed foreign proteins inherited from their father. They then injected more foreign protein into each fetus in the litter.

After this injection, scientists observed significantly more deaths among the genetically different pups than among the genetically identical pups. They repeated the experiment on a group of mice without T cells and found no difference in the rate of death between the two types of pups.


"This experiment demonstrates that activation of the mother's T cells after fetal surgery can mediate the death of genetically foreign fetuses."

Tippi MacKenzie, MD


She cautioned that there is a significant difference between her experimental mouse model and human pregnancy: If a mouse pregnancy has complications after fetal surgery, the outcome is not preterm labor but fetal death.

"That said, this mouse model is a wonderful tool to study the immune mechanisms of pregnancy complications after surgery." MacKenzie adds.

The next step for her team, "is to determine to what extent fetal interventions trigger the mother's immune response in humans, or if there is some other cause. Those studies are currently under way."

Abstract
Fetal interventions to diagnose and treat congenital anomalies are growing in popularity but often lead to preterm labor. The possible contribution of the maternal adaptive immune system to postsurgical pregnancy complications has not been explored. We recently showed that fetal intervention in mice increases maternal T cell trafficking into the fetus and hypothesized that this process also may lead to increased maternal T cell recognition of the foreign conceptus and subsequent breakdown in maternal–fetal tolerance. In this study, we show that fetal intervention in mice results in accumulation of maternal T cells in the uterus and that these activated cells can produce effector cytokines. In adoptive transfer experiments, maternal T cells specific for a fetal alloantigen proliferate after fetal intervention, escape apoptosis, and become enriched compared with endogenous T cells in the uterus and uterine-draining lymph nodes. Finally, we demonstrate that such activation and accumulation can have a functional consequence: in utero transplantation of hematopoietic cells carrying the fetal alloantigen leads to enhanced demise of semiallogeneic fetuses within a litter. We further show that maternal T cells are necessary for this phenomenon. These results suggest that fetal intervention enhances maternal T cell recognition of the fetus and that T cell activation may be a culprit in postsurgical pregnancy complications. Our results have clinical implications for understanding and preventing complications associated with fetal surgery such as preterm labor.

Footnotes
This work was supported by the California Institute for Regenerative Medicine (to A.N. and T.C.M.), National Institutes of Health/National Institute of Allergy and Infectious Diseases Grant K08 AI085042 (to T.C.M.), the National Science Foundation (to M.W.), the March of Dimes (to T.C.M.), and the Pathology and Imaging Core of the University of California San Francisco Liver Center Grant P30 DK026743.
The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of California Institute for Regenerative Medicine or any other agency of the state of California.

The online version of this article contains supplemental material.
Received September 9, 2013.
Accepted December 9, 2013.
Copyright © 2014 by The American Association of Immunologists, Inc.

Additional authors of the study are Amar Nijagal, MD, Charissa M. Wong, Tom Le, Ninnio Lescano and Qizhi Tang, PhD of UCSF.

The study was supported by funds from the California Institute for Regenerative Medicine, the National Institutes of Health (K08 AI085042), the National Science Foundation, the March of Dimes and the Pathology & Imaging Core of the UCSF Liver Center.

UCSF is the nation's leading university exclusively focused on health. It is dedicated to transforming health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy; a graduate division with world-renowned programs in the biological sciences, a preeminent biomedical research enterprise and two top-tier hospitals, UCSF Medical Center and UCSF Benioff Children's Hospital.