The ties that bind: mothers and offspring can share cells throughout life — with positive and negative effects

SEATTLE — April 30, 2008 — Cutting the umbilical cord doesn't necessarily sever the physical link between mother and child. Many cells pass back and forth between the mother and fetus during pregnancy and can be detected in the tissues and organs of both even decades later. This mixing of cells from two genetically distinct individuals is called microchimerism. The phenomenon is the focus of an increasing number of scientists who wonder what role these cells play in the body.

A potentially significant one, it turns out. Research implicates that maternal and fetal microchimerism plays both adverse and beneficial roles in some autoimmune diseases as well as the prevention of at least one cancer. This double-edged sword in turn has opened new avenues of study of the body's immune system and the possibility of developing new tests and therapies.

Two of the world's leading researchers in microchimerism are J. Lee Nelson, M.D., of Fred Hutchinson Cancer Research Center's Clinical Research Division; and V.K. Gadi, M.D., Ph.D., assistant professor of medicine at the University of Washington. Nelson also is a professor of medicine at the University of Washington. Gadi is also a research associate in the Hutchinson Center's Clinical Research Division.

In 2007, they were the first to report these potentially beneficial effects of microchimerism:

• In January, Nelson reported the first discovery that cells passed from mother to child during pregnancy can differentiate into functioning islet beta cells that produce insulin in the child. The same study also found maternal DNA in greater amounts in the blood of children and young adults with Type 1 diabetes than their healthy siblings and a control group, implying that the cells may be attempting to repair damaged tissue. There was no evidence that the mother's cells were attacking the child's insulin cells and no evidence that the maternal cells were targets of an immune response from the child's immune system. The findings could lead to new approaches to treating Type 1 diabetes. For example, if maternal microchimerism results in cells that make insulin, a mother's stem cells might be harvested and used to treat her diabetic child. Such cells would have a genetic edge over donated islet cells from a cadaver that are usually completely genetically mismatched.
  
  
• Last October, a research paper by Gadi and Nelson described findings that suggest fetal cells that persist in a woman's body long after pregnancy in some cases may reduce the woman's risk of breast cancer. The scientists examined the blood of 82 women post-pregnancy, 35 of whom had had breast cancer. They looked for male DNA in the blood, presuming it was present due to a prior pregnancy with a male. Fetal microchimerism (FMc) was found significantly more often in healthy women than women with a history of breast cancer, 43 percent versus 14 percent respectively. The scientists concluded that FMc may contribute to the reduction of breast cancer based on the hypothesis that residual fetal cells may provide immune surveillance of malignant cells in the mother. They caution that further studies are needed to confirm the theory.

Microchimerism reveals its Jekyll and Hyde personality in the case of autoimmune diseases. In the late 1990s, Nelson's group was the first to investigate microchimerism in an autoimmune disease:

• In 1996 Nelson's lab proposed that fetal microchimerism might in part explain the female predilection to autoimmune disease and they subsequently discovered elevated levels of fetal microchimerism in the blood of women with scleroderma compared to healthy women. Subsequent studies found fetal microchimerism in internal organs and in skin affected by scleroderma.
  
  
• In 1999 Nelson's group found that maternal microchimerism persists into adult life in individuals who have normal immune systems. They presumed this is due to engraftment with maternal stem cells. Stem cells can become multiple different types of cells. Researchers wondered whether maternal cells can become part of the cells that make up tissues. Scientists found maternal cells in the hearts of infants who died from heart block due to neonatal lupus and identified that most of the maternal cells were cardiac myocytes (heart muscle cells). They theorized that the maternal cells are the target of an immune attack.
  
  
• On the other hand, women with rheumatoid arthritis often have their disease improve or even disappear during pregnancy. A beneficial role of fetal microchimerism was suggested by the research finding that elevated levels of fetal microchimerism significantly correlated with pregnancy-induced amelioration of rheumatoid arthritis.

The Nelson lab has expanded its study of microchimerism into the fields of reproduction, HIV/AIDS and transplantation. For example, scientists are investigating microchimerism in complications of pregnancy, especially preeclampsia, a disorder characterized by high blood pressure in women in their third trimester of pregnancy, and in recurrent pregnancy loss.

Nelson's group also is investigating maternal microchimerism in patients with HIV and is looking at whether maternal microchimerism levels correlate with whether there is progression or non-progression to AIDS.

Transplantation of stem cells to treat some cancers results in chimerism. Graft-vs.-host disease occurs more often if the cell donor is a woman with prior pregnancies. Tests of female donor cells found they contained male microchimerism, consistent with the interpretation that fetal microchimerism contributes to graft-vs.-host disease. In kidney, pancreas and islet transplantation, Gadi, Nelson and collaborators tested serial serum samples and found that donor-specific microchimerism detection may become a useful non-invasive test for early rejection. This has led to work by several other research groups to therapeutically exploit the principles of naturally-acquired microchimerism in their selection of donors for transplantation.

The discovery that a mother's cells can turn up in her adult progeny and that fetal cells can occur in women who were once pregnant heralds the emergence of microchimerism as an important new theme in biology.

Media Contact
Dean Forbes
Fred Hutchinson Cancer Research Center
(206) 667-2896
dforbes@fhcrc.org

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Fred Hutchinson Cancer Research Center
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