Microchimerism is strongly correlated with tolerance to noninherited maternal antigens in mice

Abstract

In mice and humans, the immunologic effects of developmental exposure to noninherited maternal antigens (NIMAs) are quite variable. This heterogeneity likely reflects differences in the relative levels of NIMA-specific T regulatory (T R ) versus T effector (T E ) cells. We hypothesized that maintenance of NIMA-specific T R cells in the adult requires continuous exposure to maternal cells and antigens (eg, maternal microchimerism [MMc]). To test this idea, we used 2 sensitive quantitative polymerase chain reaction (qPCR) tests to detect MMc in different organs of NI-MA d -exposed H2 b mice. MMc was detected in 100% of neonates and a majority (61%) of adults; nursing by a NIMA ؉ mother was essential for preserving MMc into adulthood. MMc was most prevalent in heart, lungs, liver, and blood, but was rarely detected in unfractionated lymphoid tissues. However, MMc was detectable in isolated CD4 ؉ , CD11b ؉ , and CD11c ؉ cell subsets of spleen, and in lineage-positive cells in heart. Suppression of delayed type hypersensitivity (DTH) and in vivo lymphoproliferation correlated with MMc levels, suggesting a link between T R and maternal cell engraftment. In the absence of neonatal exposure to NIMA via breastfeeding, MMc was lost, which was accompanied by sensitization to NIMA in some offspring, indicating a role of oral exposure in maintaining a favorable T R > T E balance. IntroductionImmunosuppressive drugs administered to prolong graft survival increase the risk of systemic infections 1 and may encourage tumor growth. 2,3 Taking advantage of natural tolerance induced by noninherited maternal antigens (NIMAs) is one of the more promising but still relatively unexplored approaches for reducing the immunosuppressive burden in organ and stem cell transplant recipients. The clinical benefits of developmentally acquired tolerance to NIMA were first noted by Owen et al 4 more than 50 years ago. Since then, tolerogenic effects of NIMA have been documented at both T-and B-cell levels in a variety of clinical settings. [5][6][7] The basis of the NIMA benefit to allograft survival is not clear. One possible explanation is that many normal babies go on to accept, as adults, a tiny transplant of cells from their mothers acquired during ontogeny and thus are already predisposed to accept a larger NIMA ϩ organ transplant. Although fetal and maternal circulations are completely separated, fetal tissue is bathed with maternal blood in animals with a hemochorial placenta (eg, mouse and human), 8,9 creating opportunities for bidrectional transfer of mature cells as well as hematopoetic and pluripotent progenitors. [10][11][12][13][14][15] Moreover, rare maternal cells in liver can be acquired through ingestion of colostrum after birth. 15 The low frequency of maternal cells present in adult offspring (Ͻ 0.1%) is called "microchimerism" (Mc), a term also applied to rare donor cells that emigrate from graft-to-host tissue after organ transplantation. It has been suggested that Mc, while providing a miniscule antigen "load" to the host,...

Prediction of Reactivity to Noninherited Maternal Antigen in MHC-Mismatched, Minor Histocompatibility Antigen-Matched Stem Cell Transplantation in a Mouse Model

“…4C). These results suggest that the level of MMc was correlated with tolerogenic effect of the NIMA, supporting the recent report (30).…”

“…The factors that govern MMc are poorly understood, but may be of considerable clinical relevance in view of the fact that MMc has been associated with autoimmunity and allograft tolerance (30). We analyzed the levels of MMc in young adults of NIMA-exposed mice using nested PCR for MHC class II Eb d -specific DNA.…”

Microchimerism in recurrent miscarriage

“…These cells impart durable tolerance to non-inherited maternal antigens, an effect which can impact maternal health and transplant outcomes later in life. 34,35 We previously found that in normal pregnancy, cells from a woman's own mother (MP) are detectable in circulation, particularly during the third trimester. In the same study, MP microchimerism was not detected in preeclampsia, a pregnancy disorder thought by some to reflect maternal immune dysfunction.…”

Naturally acquired tolerance and sensitization to minor histocompatibility antigens in healthy family members

“…42 Similar observations were recently made in a murine F1 breeding model, in which detectable levels of maternal CD11b ϩ monocytes or CD11c expressing mDC correlated with the presence of a dominant population of transforming growth factor ␤-producing CD4 ϩ T REG in NIMA tolerant offspring. 43 From 8 donors (6 females and 2 males), sufficient numbers of PBMCs were available to determine the copresence of microchimeric cells expressing the relevant minor H alloantigen. Using DNA extracted from highly purified hematopoietic cell fractions and real-time PCR technology, we were able to demonstrate the presence of minimally one microchimeric cell type in 7 of 8 donors tested (data not shown).…”