Differential immunomodulatory effects of fetal versus maternal multipotent stromal cells
Introduction
The fetus expresses both maternal and paternal antigens and is therefore described as a “semiallograft” in relation to the maternal immune system. The mechanism by which the fetus avoids rejection and by which the functionally intact maternal immune system tolerates the fetus relates to the central question in reproductive immunology posed over 50 years ago by Medawar and Billingham [1], [2]. The decidua, which is the maternal tissue in direct contact with fetal extraembryonic tissue, is a focus of investigation in an attempt to elucidate the mechanisms involved in the delicate immunological balance of pregnancy.
Immunohistological and flow cytometric studies of first-trimester and term decidua have resulted in the identification of numerous cells of bone marrow origin, including macrophages, T lymphocytes, and uterine natural killer (NK) cells [3], [4], the proportions of which change throughout pregnancy [5]. These cells have an important role in implantation, placentation, and the maintenance of pregnancy, although their precise function remains unclear. The use of flow cytometric quantification of decidual leukocytes at term pregnancy revealed significant numbers of CD3+ T cells express the activation markers CD25, human leukocyte antigen (HLA)-DR, CD45RO, or CD69 [6], [7]. These decidual T cells include a significant number of alloreactive T cells that can respond to HLA-mismatched allogeneic peripheral blood lymphocytes (PBL) but, more strikingly, also to PBL of the fetus [8].
Several candidate cells could play a role in preventing a destructive immune reaction of maternal cells toward the fetus. Cells that have immunoregulatory potential, such as CD4+CD25bright cells, immature myeloid dendritic cells (DC), and multipotent stromal cells (MSC) are found in the placenta [9], [10], [11]. MSC have been characterized as nonhematopoietic cells because they do not express CD34 and CD45 that are able to differentiate into multiple mesenchymal lineages [12]. This type of cell is found in adult bone marrow [13] and can be isolated from first- and second-trimester fetal blood, liver, bone marrow, and lung [14], [15]. One of the characteristics of the bone marrow- and fetal liver-derived MSC is their ability to suppress alloreactive immune responses [16], [17], [18], [19], [20], [21].
We recently described the presence of MSC of both maternal and fetal origin in the human decidua, amnion, and vaginally collected amniotic fluid [22], [23]. In the present study we questioned whether MSC derived from the fetomaternal interface also demonstrated immunosuppressive activity and whether the fetal MSC were comparable in that respect to maternal MSC. We addressed this issue by adding MSC derived from second-trimester samples to primary and secondary mixed lymphocyte cultures to analyze their effect on alloreactive proliferative responses and cytokine production.
Section snippets
Samples and culture of MSC
Tissues were collected from legal terminations of pregnancy (median gestational age 20 weeks; range 17–23 weeks). Ethical approval was received from the Leiden University Medical Ethics Committee (P02/200) and informed consent was obtained from all women. To facilitate cervical ripening, all women received 2 × 200 μg misoprostol 1 ½ hours before termination of pregnancy. Second-trimester decidual tissue was collected by ultrasound-guided transcervical biopsy with a uterine exploration curette
Isolation and culture of MSC
Using flow cytometric analysis we confirmed that the cells that were isolated from the different sources had the phenotype as ascribed for MSC. The phenotype of the cultured cells was similar to that of MSC derived from adult BM [12] (i.e., uniformly positive for HLA class I, the mesenchymal antigens CD90 (Thy-1) and CD73 (SH3) and endoglin receptors CD44 and CD105 (SH2), and the β1-integrin CD29, CD54 (ICAM-1)). The cells were weakly positive for the activated leukocyte cell adhesion molecule
Discussion
The ability to modulate the alloreactive immune response has been documented for MSC derived from human bone marrow [16], [17], [26], [27], [28]. We tested whether MSC derived from the fetomaternal interface have a similar function to investigate the possibility that these cells contribute to the local immune regulation during pregnancy. To address this issue, we performed MLC in the absence and presence of MSC derived from the fetomaternal interface. We observed that an MLC of unrelated
Conclusion
In conclusion, fetal MSC derived from second-trimester amnion or amniotic fluid have the capacity to inhibit naive and antigen-experienced (memory) T cells. Administration of these cells may be helpful for enhancing engraftment of stem cells and could be used in intrauterine transplantation for hemoglobinopathies, metabolic inborn errors, and mesenchymal cell-related disorders. Further investigation into the functional role of these cells is warranted for understanding the immunology of
Acknowledgments
This work was supported by the National Reference Center for Histocompatibility Testing.
We thank W. Beekhuizen of the Center of Human Reproduction in Leiden for collecting the amniotic fluid and Prof. Dr. A. Brand and Prof. Dr. F. Koning for critically reading the manuscript.
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D.L. Roelen and B.J. van der Mast contributed equally to the manuscript.