|Home | About | Journals | Submit | Contact Us | Français|
Maternal-fetal cellular trafficking during pregnancy results in bidirectional microchimerism with potentially long-term consequences for the mother and her fetus. Exposure of the fetus to maternal cells results in tolerance to non-inherited maternal antigens (NIMA) and may therefore impact transplant outcomes. We investigated the rates of graft failure and retransplantation after parental liver transplantation in pediatric recipients with biliary atresia (BA), a disease with high levels of maternal microchimerism. We observed significantly lower rates of graft failure and retransplantation in BA recipients of maternal livers compared with BA recipients of paternal livers. Importantly, recipients without BA had equivalent transplant outcomes with maternal and paternal organs, suggesting that increased maternal microchimerism in BA patients may be the underlying etiology for tolerance. These results support the concept that prenatal exposure to NIMA may have consequences for living-related organ transplantation.
Maternal-fetal cellular trafficking (MFCT) is the bidirectional passage of cells between a mother and her fetus, resulting in long-lived maternal cells in the fetus1 and of fetal cells in the mother.2 It has been reported that the presence of maternal cells in the fetus (maternal microchimerism) promotes the formation of regulatory T cells that suppress the fetal immune response to non-inherited maternal antigens (NIMA)3 and is therefore an important component of maternal-fetal tolerance. It is possible that this tolerance may be long-lived and have an impact on the success of organ transplantation when the mother serves as the donor. While intriguing, the results in several transplantation settings have been variable. A beneficial effect of NIMA exposure has been reported in bone marrow transplantation,4,5 but results in the setting of kidney transplantation have been mixed.6-8
Biliary atresia (BA) is a disease characterized by inflammation of the biliary tree resulting in obliteration of the bile ducts and neonatal liver failure, often requiring liver transplantation. The observation that patients with BA have an increased number of maternal cells in their livers9-11 led us to hypothesize that increased maternal microchimerism may lead to improved long-term allograft tolerance in this setting. We examined a national database of living related liver transplants in children between the ages of 0–6 y over a 15-year period, and found improved graft survival specifically among BA patients who received a maternal liver compared with those that received a paternal liver.12 The beneficial effect of maternal liver transplantation was only seen when the underlying disease was BA and not for other pediatric liver diseases, suggesting that maternal microchimerism may impact transplant outcomes. Our findings were also independent of female donor gender, since BA patients receiving organs from female deceased donors did not have different outcomes. We observed consistent results when examining graft rejection episodes from patients treated at our institution: BA recipients of maternal livers had a lower rate of refractory graft rejection compared with recipients of paternal livers, whereas this difference was not observed among non-BA recipients.12 These results indicate that BA patients have differential tolerance to maternal compared with paternal antigens and may be useful in patient counseling.
An alternative explanation for our findings is that paternal livers are more easily rejected in BA patients. The etiology of BA is unknown, and it has been speculated that maternal cells contribute to disease pathogenesis, especially since the predominant maternal cell type that is elevated in livers of BA patients is cytotoxic CD8+ T cells.13 One potential model, therefore, is that maternal cells may reject paternal antigens on hepatocytes to cause BA and would therefore also reject those antigens on a paternal liver graft. However, this model would be incomplete since our study showed that 90% of paternal livers are not rejected in BA patients. In addition, it was recently reported that a high proportion of pediatric recipients of parental living donor liver transplants (the majority of whom have BA) could undergo withdrawal of their immunosuppression without experiencing rejection.14 Ultimately, functional assays of isolated maternal cells from BA patients will be necessary to understand the link between the pathogenesis of BA and maternal microchimerism.
An interesting question raised by our study is whether the tolerogenic effect of NIMA exposure diminishes over time. It is possible that maternal microchimerism is highest in younger patients and therefore the tolerogenic effect of NIMA exposure should be most apparent in this age group. If so, the fact that BA patients are younger than non-BA patients at the time of transplantation may be an important confounding factor in our results. To address this issue directly, we performed subgroup analysis in various age groups (0–1 y, 0–2 y, 0–6 y and 0–18 y) and consistently observed improved outcomes with maternal transplantation only in BA patients, supporting our conclusion that there is altered tolerance to maternal antigens specifically in this disease.
Although we did not directly measure maternal microchimerism levels in our study, the observation that there are improved outcomes with maternal liver transplantation only in BA patients suggests that increased levels of maternal microchimerism in this disease impact tolerance. Since maternal microchimerism must also be present in non-BA patients, albeit at lower levels, this result suggests that there is a threshold level of chimerism required for tolerance induction. This idea is supported by the observation that in NIMA-exposed animals, there is a positive correlation between the level of maternal microchimerism and the suppression of an anti-NIMA immune response.15 Importantly, a threshold level of maternal microchimerism correlates with high levels of regulation in NIMA-exposed animals.15 A similar threshold concept has been reported for tolerance induction after in utero transplantation of hematopoietic cells.16 These observations support the crucial need for a dedicated study of the levels of maternal cells in BA patients and subsequent transplant outcomes.
Our results also raise broader questions regarding the function of MFCT in human disease. In addition to BA,11,13 increased maternal microchimerism has been identified in numerous pediatric diseases including type I diabetes,17,18 neonatal lupus-syndrome congenital heart block,19 myopathies,20 dermatomyositis,21,22 Hirschsprung disease23 and pityriasis lichenoides.24 It is not known whether maternal cells contribute to disease or proliferate in response to tissue injury in any of these diseases. We have also recently reported increased maternal microchimerism after open fetal surgery in patients with myelomeningocele compared with patients who had postnatal repair, suggesting increased recruitment or increased proliferation of maternal cells after fetal intervention.25 These results are consistent with our finding of increased maternal cells after fetal intervention in mice26 and we are currently exploring whether such alterations in microchimerism impact maternal-fetal tolerance during pregnancy.
The role of MFCT in maternal and fetal health remains a fascinating yet unanswered question. Our results support the idea that maternal microchimerism correlates with long-term tolerance in the setting of liver transplantation for biliary atresia. However, alterations in microchimerism may have beneficial or harmful consequences depending on the disease setting. A better understanding of the cellular mechanisms that lead to increased microchimerism and improved tolerance in BA will be crucial to achieve further advances in this field.
Nijagal A, Fleck S, Hills NK, Feng S, Tang Q, Kang SM, et al. Decreased risk of graft failure with maternal liver transplantation in patients with biliary atresia Am J Transplant 2012 12 409 19 doi: 10.1111/j.1600-6143.2011.03895.x.
Previously published online: www.landesbioscience.com/journals/chimerism/article/20152