(Micro)Chimerism & Treatment: Immune Tolerance, Transplantation, and Precision Therapeutics
Pregnancy-derived microchimerism exerts durable immunological and clinical consequences that extend from early development to transplantation and autoimmunity. Bidirectional trafficking of maternal and fetal cells establishes antigen-specific tolerance or sensitization shaped by HLA disparity, with implications for transplant compatibility, graft-versus-leukemia effects, and longterm immune regulation. Mechanistic frameworks linking non-inherited maternal antigens and inherited paternal antigens to immune education underscore how gestational exposure can promote either tolerance or pathogenic alloimmunity. In parallel, emerging antigen-specific therapeutic tools like CAR T cells provide experimental avenues to directly test the contribution of rare chimeric populations to autoimmune disease. Technological innovation is central to these advances: high-resolution single-cell transcriptomics and novel bioinformatic tools now enable detection of exceedingly rare foreign-genotype cells across blood, tissues, and transplant samples, revealing diverse cellular fates and lifelong persistence. Expansion and characterization of microchimeric populations further suggests developmental routes for durable engraftment and biological functionality. This interdisciplinary session highlights microchimerism as a biologically embedded determinant of immunity, disease risk, and therapeutic opportunity and provides insight into fascinating technological developments.
Wednesday, 27.05.2026, Day 1
Time: 14:00 – 15:30
Consequences of pregnancy-derived microchimerism for outcome after transplantation
Michael Eikmans
Leiden University Medical Center, The Netherlands
Microchimerism can cause immune recognition between mother and fetus. Differences in human leukocyte antigen (HLA) genes between two hosts is a main driver of immune reactions. The child inherits one set of HLA genes from the mother and one from the father. The mother may develop immunity by forming antibodies and effector- and regulatory T cells, which are specific against the inherited paternal antigens (IPA) of the fetus. Vice versa, T cells from the fetus may show reactivity to non-inherited maternal antigens (NIMA).
Likewise, exposure of a recipient to a transplanted organ or cells from a genetically different individual leads to immune reactions. Previous studies have emphasized the possible consequence of microchimerism for outcome of transplantation performed later in life. For instance, immune recognition by the pregnant woman may lead to HLA antibody development, forming a hurdle when a transplant is given containing HLA antigens to which those antibodies are directed to. Alternatively, maternal exposure during pregnancy in the womb leads to immune tolerance. If a patient, having developed tolerance toward the NIMA, is offered a donor kidney containing a mismatched antigen that is the same as the NIMA, there is no significant negative impact on transplant outcome.
In this lecture I focus on maternal microchimerism (mMC) in the fetus. Umbilical cord blood (UCB) from the newborn can be used as a source for cell transplantation in patients suffering from leukemia. Clinical studies provided indirect evidence that mMC cells in fetal blood mediate graft-versus-leukemia effects in the recipient after UCB transplantation. Attempts for enriching these cells are discussed along with questions including: which cell types are these chimeric cells? How are these chimeric cells maintained and not cleared by the host’s immune system? Why would these cells not directly attack host cells, but would exert alloreactivity in a recipient?
Strategies to test the role of microchimerism in autoimmune disease through antigen-specific therapeutic development
Anne M. Stevens
Executive Medical Director, Century Therapeutics
Adjunct Clinical Professor, Pediatric Rheumatology, Stanford University
Retired Professor, Pediatric Rheumatology, University of Washington
Attending Physician, Pediatric Rheumatology, Renown Regional Medical Center, Reno, NV
Maternal and fetal microchimerism (MMc, FMc) derived during pregnancy have been associated with various aspects of health and disease. In the context of interactive genetic backgrounds, both FMc and MMc have been implicated in the triggering and perpetuation of chronic autoimmune diseases. Functional studies in vitro and in mouse models support a role for loss of allogeneic T cell regulation of fetal-maternal tolerance contributing to chronic inflammation. Novel strategies to target cells with an antigen-specific CAR T cell or bispecific large molecule therapeutics opens up a pathway toward treatment of autoimmunity via depletion of small numbers of pathogenic chimeric cells expressing non-inherited maternal or fetal antigens. Innovative therapeutic development approaches targeting antigen-specific T and B lymphocytes will be discussed with relevance to applying technologies to definitively test roles of MMc and FMc in the pathogenesis of autoimmune disease.
A novel approach to investigate breastmilk T cell antigen-specific responses
Blair Armistead
Yonghou Jiang1, Jennifer E. Stolarczuk2, Sharon Kung2, John Houck1, Victoria L. Campbell3, David M. Koelle3,4,5, Alisa Kachikis2, Whitney E. Harrington1,7,8, Blair Armistead1,8
1 Seattle Children’s Research Institute, Center for Global Infectious Disease Research, Seattle, WA, USA
2 University of Washington School of Medicine, Department of Obstetrics and Gynecology, Seattle, WA, USA
3 University of Washington School of Medicine, Department of Medicine, Seattle, Washington, USA
4 Fred Hutchinson Cancer Research Center, Vaccine and Infectious Disease Division, Seattle, Washington, USA
5 University of Washington School of Medicine, Department of Laboratory Medicine & Pathology, Seattle, Washington, USA
6 Benaroya Research Institute, Seattle, Washington, USA
7 University of Washington, Department of Global Health, Seattle, Washington, USA
8 University of Washington School of Medicine, Department of Pediatrics, Seattle, WA USA
Abstract
Breastmilk plays a pivotal role in infant health and development, providing both nutritional and immunological benefits. In addition to protective antibodies, breastmilk contains immune cells, including T cells, which have an unknown role in human infant immunity. However, multiple studies in animals have shown that milk-derived T cells can traffic to peripheral organs of nursing offspring as a form of maternal microchimerism (MMc) and provide protection from infection. Further study is needed to understand the potential of breastmilk T cells to exert pathogen-specific effector functions at the maternal-infant interface. To-date, direct ex vivo functional analyses and T cell receptor sequencing of breastmilk T cells have been limited by low T cell frequency. To overcome this barrier, we optimized a method to expand breastmilk T cells in culture using cell sorting and mitotic stimulation. With this approach, we generated expanded breastmilk T cell (EBM T cell) cultures from n=4 lactating women, resulting in a ~1,000-fold increase in T cells from the original sample. Because each donor reported receipt of SARS-CoV-2 (SARS2) mRNA vaccination and/or history of SARS2 infection, we used SARS2 Spike as a model for detecting antigen-specific responses in EBM T cell cultures. In EBM T cell cultures from 2 of 2 donors tested, we identified SARS2 Spike-specific CD8+ T cells using an HLA-matched, Spike-loaded tetramer. To assess antigen-specific functional responses, we stimulated EBM T cells from one donor with a SARS2 Spike peptide pool, using autologous irradiated PBMC for antigen presenting function. Spike-stimulated EBM T cells contained CD4+ and CD8+ T cells expressing activation-induced markers, suggesting that their antigen-specific functionality was preserved. Together, our findings show that our novel approach is a valuable platform for investigating pathogen-specific responses in breastmilk T cells, with relevance to the study of breastmilk-derived MMc in infants.
Is the skin the preferred target of twin microchimerism in mice in all cross combinations: allogeneic, congenic and semi-allogeneic?
Yoan Ghaffar
Yoan GHAFFAR1, Chahinez ARIF1, Mathilde GIASSI 1, Marielle MARTIN1, Isabelle AUGER1, Catherine DUEZ1 and Nathalie LAMBERT1.
INSERM U1097 ARTHEMIS Aix Marseille University, France
During pregnancy, bidirectional cell exchange—especially between twins—represents a significant but often overlooked source of microchimerism. This mouse study investigates two key questions: What are the preferred niches for littermate microchimeric cells (LMc), and what factors influence the quantity of cells transferred between twins?
Previous work by the team showed that an embryo’s location in the uterine horn affects the amount of LMc it receives. Here, we examine how genetic relationships (allogeneic, semi-allogeneic, congenic) influence the passage and persistence of LMc from embryonic to adult stages. We use crosses where the father is heterozygous for the TdTomato fluorescence gene, allowing tracking of TdTomato+ LMc cells in offspring that did not inherit the gene. Crosses are as follows : C57BL6 X C57BL6-Tom+ (congeneic), DBA/2 X C57BL6-Tom+ (allogeneic), and D2BL6 X C57BL6-Tom+ mice, with respectively 6, 17, and 22 offspring dissected at embryonic, young adult, or older adult stages. About 20 tissues per offspring are tested for TdTomato presence via quantitative PCR, and organ sections are preserved for microscopy.
Preliminary results show that, as previously observed in semi-allogeneic crosses, the skin is the preferred niche for LMc in allogeneic crosses with respectively 4/4 embryos, and 5/5 of young adults. Congenic crosses have not yet been tested. Further analysis is needed to characterize these skin-resident cells. These findings echo earlier lab work identifying cells from a vanished twin in a 40-year-old man with scleroderma-like syndrome, suggesting that twin microchimerism may play a role in skin-targeted autoimmune diseases such as scleroderma.
An optimized flow cytometry-based method for the isolation of potential microchimeric maternal cells in human mesenchymal stem cells using monoclonal HLA class I specific antibodies
Bernadette L. Bramreiter
Bernadette L. Bramreiter1, Rachel C. Quilang2, Carin van der Keur2, Anne Wagenmakers2, Katja Sallinger1, Emiel Slaats1, Julia Schönberger1, Katharina Schuch1, Hyun-Dong Chang3,4, Dave Roelen2, Thomas Kroneis1, Michael Eikmans2
1Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical
University of Graz, Graz, Austria
2Department of Immunology, Leiden University Medical Center, Leiden, Netherlands
3German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
4Institute for Biotechnology, Technische Universität, Berlin, Germany
Objectives
Microchimerism (MC) is defined as the presence of a small population of genetically distinct cells originating from another individual. During pregnancy, cells are trafficking across the feto-maternal interface in both directions, resulting in maternal and fetal MC (mMC, fMC). Microchimeric cells have been reported to exhibit stem and progenitor cell-like properties, suggesting that stem cell compartments may contribute to MC persistence. However, the identity and trafficking pathways of the cells remain poorly understood. This study aimed to develop and optimize a sex-unbiased flow cytometry-based method to isolate viable potential mMC cells from human fetal mesenchymal stem cell (MSC) populations using monoclonal HLA class I-specific antibodies (HuMoAbs).
Methods
HuMoAbs of IgG and IgM isotypes were generated at LUMC from transformed B lymphocytes. Thirteen HuMoAbs targeting HLA-A and HLA-B (e.g. A3 and B8) were selected and validated for the separation of maternal and fetal cells. To improve population discrimination and detection sensitivity, maternal specific HuMoAbs were separately conjugated to PE or FITC and used simultaneously for staining. PE/FITC double-positive cells were considered of maternal origin.