{
  "abstract": "Objectives Up 50% of pregnancies in women with systemic lupus erythematosus (SLE) is complicated by adverse outcomes, such as preterm birth, fetal growth restriction and pre-eclampsia. The underlying biological mechanisms remain unclear, but the consistent risk across successive pregnancies suggests a fundamental defect in maternal-fetal tolerance. This unique immunological tolerance results from interaction between fetal placental cells, like syncytiotrophoblasts (STB) and extravillous trophoblasts (EVT), and maternal immune cells at two maternal-fetal interfaces (MFI): the placental villi with STB bathing in maternal blood, and the decidua where EVT interact with decidual immune cells. Since these interfaces cannot be studied in vivo, we developed two novel in vitro organoid-based models to replicate their unique architectures and enable investigation of maternal-fetal tolerance in SLE.Methods To model the STB-blood interface, we cultured JEG-3 cells or trophoblast stem cells (TSC) on collagen-coated Cytodex beads in a rotating wall vessel bioreactor, promoting differentiation into STB-like cells. Peripheral blood mononuclear cells (PBMC) are then added in this rotating system, which mimics the flow of maternal blood along STBs, creating a STB-immune (STB-I) model. For the decidual EVT interface, TSC were grown as organoids in Matrigel and differentiated into EVT, which invade the Matrigel similar to in vivo migration. PBMC or decidual immune cells were then added to create the EVT-immune (EVT-I) model, enabling analysis of EVT-immune interactions.Results In the STB-I model, both JEG-3 and TSC adhered to beads and differentiated into STB-like cells, with TSC showing faster and more robust syncytialisation. PBMC addition increased IL-10 levels in the culture supernatant, indicating formation of an anti-inflammatory milieu. In the EVT-I model, PBMC from certain donors inhibited organoid formation or EVT invasion, depending on the timepoint they were added. Notably, within the PBMC, T cells in contact with EVT showed increased HELIOS expression when compared to T cells not in contact with EVT.Conclusions With this work we have generated two novel 3D organoid-based model, each recapitulating a unique maternal-fetal interface, to dissect the mechanisms of maternal-fetal tolerance. This offers new avenues to understand and ultimately predict or prevent pregnancy complications in women with and without SLE.",
  "authors": [
    {
      "affiliations": [
        "Amsterdam UMC, Department of Rheumatology and Clinical Immunology, Amsterdam, The Netherlands",
        "Amsterdam UMC, Department of Experimental Immunology, Amsterdam, The Netherlands",
        "Amsterdam UMC, Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam, The Netherlands",
        "Amsterdam UMC, Amsterdam Reproduction and Development Institute, Amsterdam, The Netherlands"
      ],
      "name": "Wendy Dankers"
    },
    {
      "affiliations": [
        "Amsterdam UMC, Department of Rheumatology and Clinical Immunology, Amsterdam, The Netherlands",
        "Amsterdam UMC, Department of Experimental Immunology, Amsterdam, The Netherlands"
      ],
      "name": "Dennis Bakkenes"
    },
    {
      "affiliations": [
        "Amsterdam UMC, Amsterdam Reproduction and Development Institute, Amsterdam, The Netherlands",
        "Amsterdam UMC, Reproductive Biology Laboratory, Amsterdam, The Netherlands"
      ],
      "name": "Jantine Van Voorden"
    },
    {
      "affiliations": [
        "Amsterdam UMC, Amsterdam Reproduction and Development Institute, Amsterdam, The Netherlands",
        "Amsterdam UMC, Reproductive Biology Laboratory, Amsterdam, The Netherlands"
      ],
      "name": "Souad Boussata"
    },
    {
      "affiliations": [
        "Amsterdam UMC, Amsterdam Reproduction and Development Institute, Amsterdam, The Netherlands",
        "Amsterdam UMC, Reproductive Biology Laboratory, Amsterdam, The Netherlands"
      ],
      "name": "Remco Keijser"
    },
    {
      "affiliations": [
        "Amsterdam UMC, Department of Rheumatology and Clinical Immunology, Amsterdam, The Netherlands",
        "Amsterdam UMC, Department of Experimental Immunology, Amsterdam, The Netherlands"
      ],
      "name": "Jikke Van Ruitenbeek"
    },
    {
      "affiliations": [
        "Amsterdam UMC, Department of Rheumatology and Clinical Immunology, Amsterdam, The Netherlands",
        "Amsterdam UMC, Department of Experimental Immunology, Amsterdam, The Netherlands"
      ],
      "name": "Danique Biskop"
    },
    {
      "affiliations": [
        "Amsterdam UMC, Amsterdam Reproduction and Development Institute, Amsterdam, The Netherlands",
        "Amsterdam UMC, Department of Obstetrics and Gynaecology, Amsterdam, The Netherlands"
      ],
      "name": "Marjon De Boer"
    },
    {
      "affiliations": [
        "Amsterdam UMC, Department of Rheumatology and Clinical Immunology, Amsterdam, The Netherlands",
        "Amsterdam UMC, Department of Experimental Immunology, Amsterdam, The Netherlands",
        "Amsterdam UMC, Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam, The Netherlands"
      ],
      "name": "Irene Bultink"
    },
    {
      "affiliations": [
        "Amsterdam UMC, Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam, The Netherlands",
        "Amsterdam UMC, Amsterdam Reproduction and Development Institute, Amsterdam, The Netherlands",
        "Amsterdam UMC, Reproductive Biology Laboratory, Amsterdam, The Netherlands"
      ],
      "name": "Gijs Afink"
    },
    {
      "affiliations": [
        "Amsterdam UMC, Department of Rheumatology and Clinical Immunology, Amsterdam, The Netherlands",
        "Amsterdam UMC, Department of Experimental Immunology, Amsterdam, The Netherlands",
        "Amsterdam UMC, Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam, The Netherlands"
      ],
      "name": "Lisa Van Baarsen"
    }
  ],
  "title": "PO:12:326 Developing two distinct organoid-based models to study failing maternal-fetal tolerance in systemic lupus erythematosus",
  "uid": "b92da8f1-931e-524f-a649-fb0888bd4728"
}