title: Mesenchymal Stromal Cells Prevent Allostimulation In Vivo and Control Checkpoints of Th1 Priming: Migration of Human DC to Lymph Nodes and NK Cell Activation.
abstract: Although the immunomodulatory potency of mesenchymal stromal cells (MSC) is well established, the mechanisms behind are still not clear. The crosstalk between myeloid dendritic cells (mDC) and natural killer (NK) cells and especially NK cell-derived interferon-gamma (IFN-γ) play a pivotal role in the development of type 1 helper (Th1) cell immune responses. While many studies explored the isolated impact of MSC on either in vitro generated DC, NK, or T cells, there are only few data available on the complex interplay between these cells. Here, we investigated the impact of MSC on the functionality of human mDC and the consequences for NK cell and Th1 priming in vitro and in vivo. In critical limb ischemia patients, who have been treated with allogeneic placenta-derived mesenchymal-like stromal cells (PLX-PAD), no in vivo priming of Th1 responses toward the major histocompatibility complex (MHC) mismatches could be detected. Further in vitro studies revealed that mDC reprogramming could play a central role for these effects. Following crosstalk with MSC, activated mDC acquired a tolerogenic phenotype characterized by reduced migration toward CCR7 ligand and impaired ability to stimulate NK cell-derived IFN-γ production. These effects, which were strongly related to an altered interleukin (IL)-12/IL-10 production by mDC, were accompanied by an effective prevention of Th1 priming in vivo. Our findings provide novel evidence for the regulation of Th1 priming by MSC via modulation of mDC and NK cell crosstalk and show that off-the-shelf produced MHC-mismatched PLX-PAD can be used in patients without any sign of immunogenicity.
authors.affiliation: Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité University Medicine, Berlin, Germany.|Berlin-Brandenburg School for Regenerative Therapies (BSRT), Charité University Medicine, Berlin, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Consentius
authors.affiliation: Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité University Medicine, Berlin, Germany.|Institute for Medical Immunology, Charité University Medicine, Berlin, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Akyüz
authors.affiliation: Franziskus Hospital, Berlin, Germany.
authors.forename: J A
authors.initials: JA
authors.lastname: Schmidt-Lucke
authors.affiliation: Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité University Medicine, Berlin, Germany.|Department for Cardiology, CVK, Charité University Medicine, Berlin, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Tschöpe
authors.affiliation: Pluristem Therapeutics, Inc, Haifa, Israel.
authors.forename: L
authors.initials: L
authors.lastname: Pinzur
authors.affiliation: Pluristem Therapeutics, Inc, Haifa, Israel.
authors.forename: R
authors.initials: R
authors.lastname: Ofir
authors.affiliation: Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité University Medicine, Berlin, Germany.|Department for Nephrology and Intensive Care, CVK, Charité University Medicine, Berlin, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Reinke
authors.affiliation: Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité University Medicine, Berlin, Germany.|Institute for Medical Immunology, Charité University Medicine, Berlin, Germany.
authors.forename: H-D
authors.initials: HD
authors.lastname: Volk
authors.affiliation: Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité University Medicine, Berlin, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Juelke
mesh_terms: D002450:Cell Communication / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006801:Humans; D007111:Immunity, Cellular; D056747:Immunomodulation; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D059630:Mesenchymal Stem Cells / Q000276:immunology* / Q000378:metabolism; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism; D010920:Placenta / Q000166:cytology / Q000378:metabolism; D011247:Pregnancy; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism
chemical_list: D016753:Interleukin-10; D007371:Interferon-gamma
keywords: IL-10; Immunomodulation; Mesenchymal stromal cells; Myeloid dendritic cells; Natural killer cells; Th1 priming