Placental Trophoblast from Successful Human Pregnancies Expresses the Tolerance Signaling Molecule, CD200 (OX-2)*

Authors

  • David A. Clark,

    1. Departments of Medicine, Molecular Medicine and Pathology, and Ob-Gyn, McMaster University, Hamilton, Ontario;
    2. Toronto General Research Institute, Toronto, Ontario;
    3. Toronto General Research Institute, Transplantation Immunology Program, and Institute of Medical Sciences, School of Graduate Studies, University of Toronto, Ontario;
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  • Anja Keil,

    1. Departments of Medicine, Molecular Medicine and Pathology, and Ob-Gyn, McMaster University, Hamilton, Ontario;
    2. Department of Obstetrics, Friedrich-Schiller-Universitat, Jena, Germany
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  • Zhiqi Chen,

    1. Toronto General Research Institute, Toronto, Ontario;
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  • Udo Markert,

    1. Department of Obstetrics, Friedrich-Schiller-Universitat, Jena, Germany
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  • Justin Manuel,

    1. Departments of Medicine, Molecular Medicine and Pathology, and Ob-Gyn, McMaster University, Hamilton, Ontario;
    2. Toronto General Research Institute, Toronto, Ontario;
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  • Reginald M. Gorczynski

    1. Toronto General Research Institute, Transplantation Immunology Program, and Institute of Medical Sciences, School of Graduate Studies, University of Toronto, Ontario;
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  • *

    Supported by a grant from the Canadian Institutes for Health Research.

Address reprint requests to David A. Clark, Rm 3V39 McMaster University Medical Center, 1200 Main St. West, Hamilton, Ontario L8N 3Z5, Canada. E-mail: clarkd@mcmaster.ca

Abstract

Problem: Th1 cytokine-dependent abortions in the CBA × DBA/2 mouse model have been linked to down-regulation of expression of the CD200 (OX-2) ‘tolerance’ signal on trophoblast and in decidua prior to onset of the abortion process. Abortions could be prevented by administration of a soluble CD200. Is CD200 expressed on trophoblast in successful human pregnancy?

Method of study: As one cannot easily obtain trophoblasts in large quantities from successful human pregnancies in the first trimester prior to the onset of the abortion process at 6 weeks gestation, we examined as a first step, trophoblast isolated from term placentae (i.e. successful pregnancies). CD9 trophoblasts were isolated by affinity column and stained for intracellular cytokeratin, and surface CD200 using PE-anti-human CD200 monoclonal antibody. mRNA was extracted from CD9+ and CD9 cells and tested by reverse transcription–polymerase chain reaction for CD200 mRNA. CD9 placental cells were separated by velocity sedimentation and test for CD200-dependent suppression of an allogeneic human mixed lymphocyte culture where cytotoxic T cell (CTL) generation, and Th1 → Th2 cytokine production shift were measured.

Results: CD9 but not CD9+ placental cell populations contained cells with mRNA for CD200, both a normal length transcript and a truncated transcript. Flow cytometry showed a CD200+ cytokeratin+ moderate-to-large-sized cell population compatible with trophoblasts and a smaller subset of cytokeratin cells that expressed CD200 at normal and at high levels. The moderate-sized population proved most potent at inhibiting CTL generation and caused a Th1→Th2 cytokine shift. These effects were blocked by monoclonal anti-CD200.

Conclusions: A subpopulation of cytokeratin+ placental trophoblasts express bioactive CD200 able to alter maternal immune responses in a favorable (Th2 > Th1) direction. Two populations of CD200+ small- and medium-small-sized cytokeratin placental cells remain to be identified. Studies of karyotyped first trimester elective termination and spontaneous miscarriage tissues are needed.

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