How Active Immune Tolerance Makes Pregnancy Possible

How Active Immune Tolerance Makes Pregnancy Possible


Understanding of mouse immune-system response to specific fetal antigens also may provide insight into issues that arise during human pregnancies.

The concept of pregnancy makes no sense - at least not from an immunological point of view. After all, a fetus, carrying half of its father's genome, is biologically distinct from its mother. The fetus is thus made of cells and tissues that are very much not "self" - and not-self is precisely what the immune system is meant to search out and destroy.

Women's bodies manage to ignore this contradiction in the vast majority of cases, making pregnancy possible. Similarly, scientists have generally paid little attention to this phenomenon - called "pregnancy tolerance" - and its biological details.

Now, a pair of scientists from the California Institute of Technology (Caltech) have shown that females actively produce a particular type of immune cell in response to specific fetal antigens - immune-stimulating proteins - and that this response allows pregnancy to continue without the fetus being rejected by the mother's body.

Their findings were detailed in a recent issue of the Proceedings of the National Academy of Sciences (PNAS).

"Our finding that specific T regulatory cells protect the mother is a step to learning how the mother avoids rejection of her fetus. This central biological mechanism is important for the health of both the fetus and the mother," says David Baltimore, Caltech's Robert Andrews Millikan Professor of Biology, recipient of the 1975 Nobel Prize in Physiology or Medicine, and the principal investigator on the research.

Scientists had long been "hinting around at the idea that the mother's immune system makes tolerance possible," notes paper coauthor Daniel Kahn, a visiting associate in biology at Caltech, and an assistant professor of maternal-fetal medicine at the University of California, Los Angeles (UCLA). What they didn't have were the details of this tolerance - or proof that it was immune-related.

Now they do. To pin down those details, the two scientists began looking at the immune system's T regulatory cells (Tregs) in a strain of inbred mice that are all genetically identical - except for one seemingly tiny detail. Male mice - including male fetuses - carry on their cells' surfaces a protein known as a "minor transplantation antigen." Female mice lack this antigen.

Under normal circumstances, this antigen's existence isn't a problem for the male fetuses because the pregnancy tolerance phenomenon kicks in and protects them from any maternal immune repercussions.

To demonstrate the role of Tregs, Baltimore and Kahn used a drug to selectively target and destroy the cells. If the Tregs were indeed the source of pregnancy tolerance, they reasoned, their destruction would give the immune system free rein to go after the antigen-laden fetuses.

"In this case," says Kahn, "we knew the only possible immune response would be against the males - that the males would be at risk."
Indeed they were. When Baltimore and Kahn looked at the offspring of mice who'd been treated with the toxin, they found that fewer of the male fetuses survived to birth; those males that did survive were of significantly lower birthweight, presumably because of the inflammation caused by the mother's immune response to that single antigen.

"These T cells are functioning in an antigen-specific manner," Kahn notes. "In other words, their function requires the presence of the specific fetal antigens."

In their studies of these animals, the scientists also found that pregnancy tolerance "develops actively as a consequence of pregnancy," says Kahn. "The mice are not born with it." Indeed, virgin mice showed no signs of these pregnancy-specific Treg cells. Conversely, the cells were found in larger numbers in those individual mice that had given birth to more male babies, with the level of Treg cells increasing with the number of male births.

The next step, Kahn adds, is to look at Tregs and their role in pregnancy tolerance in humans - a line of research that may lead to new insights into such pregnancy-related conditions as preeclampsia, in which high blood pressure and other symptoms develop in the second half of pregnancy. Preeclampsia is a major cause of maternal mortality around the world.

"There's a lot to be learned," he says. "Pregnancy is often ignored in research because it's usually successful, and because - from an immunologic standpoint - it has such complexity. Until now, it's been difficult to grab a handle on how the immunology of pregnancy really works."

The work described in the PNAS article, "Pregnancy induces a fetal antigen-specific maternal T regulatory cell response that contributes to tolerance," was supported in part by a research grant from the Skirball Foundation. Kahn is supported by the National Institutes of Health's Building Interdisciplinary Research Careers in Women's Health Center at UCLA.

Rogue stem cells capable of kick-starting melanoma skin cancer development discovered

Rogue stem cells capable of kick-starting melanoma skin cancer development discovered


Scientists identify melanoma stem cells

Researchers at Stanford University School of Medicine in the US have discovered that rogue stem cells appear to be capable of kick-starting the development of melanoma skin cancer in humans.

Many researchers think that tumour growth is fuelled by a subset of 'immortal' cancer stem cells. When they multiply, they produce 'bulk' tumour cells, as well as more stem cells.

Cancer stem cells may explain why cancer can return in patients who first appear to have been successfully treated. Although treatments such as chemotherapy and radiotherapy are effective against bulk tumour cells, they don't appear to target cancer stem cells.

Cancer stem cells have been identified in a number of different types of cancer, but until now, they have not been discovered in melanoma.

The researchers analysed protein molecules on the surface of cells from melanoma samples that had been taken from patients at the Stanford Cancer Centre. They found that between 2.5 and 41 per cent of cells had a protein called CD271 on their surface.
The researchers then transplanted human melanoma cells into mice, some of which received cells with CD271 on their surface while others received cells which lacked CD271.

Cells with CD271 were much more likely to grow into tumours than cells without the protein, suggesting they may have stem cell-like properties.

All but one of the new tumours arising from CD271 cells contained a mixture of CD271-positive and CD271-negative melanoma cells.

This shows that the stem cells could produce bulk tumour cells as well as new stem cells - a classic hallmark of stem cell behaviour.

The team also found that melanoma stem cells lack proteins that are targeted by immunotherapy - a treatment that harnesses the patient's immune system to destroy cancer cells. This helps to explain why some melanomas don't respond to immunotherapy, and could shape the design of future therapies for the disease.

Commenting on the discovery, which is published in the journal Nature, lead researcher Dr Alexander Boiko, a post-doctoral fellow at Stanford, revealed: "These cells lack the traditional melanoma cell surface markers targeted by these treatments. Without wiping out the cells at the root of the cancer, the treatment will fail.

"This could be the reason why we often see melanoma patients relapsing and coming back to the clinic. Our research indicates that it may be more appropriate to also target cells expressing CD271."

Dr Kat Arney, science information manager at Cancer Research UK, said: "Researchers are finding cancer stem cells in many different types of tumour, and many scientists believe they are at the heart of a wide range of cancers.

"Understanding these elusive 'immortal' cells will be the key to developing more effective treatments for cancer in the future, so this research is an important step towards beating melanoma."