title: Human placenta-derived adherent cells induce tolerogenic immune responses.
abstract: Human placenta-derived adherent cells (PDAC cells) are a culture expanded, undifferentiated mesenchymal-like population derived from full-term placental tissue, with immunomodulatory and anti-inflammatory properties. PDA-001 (cenplacel-L), an intravenous formulation of PDAC cells, is in clinical development for the treatment of autoimmune and inflammatory diseases. To elucidate the mechanisms underlying the immunoregulatory properties of PDAC cells, we investigated their effects on immune cell populations, including T cells and dendritic cells (DC) in vitro and in vivo. PDAC cells suppressed T-cell proliferation in an OT-II T-cell adoptive transfer model, reduced the severity of myelin oligodendrocyte glycoprotein peptide-induced experimental autoimmune encephalomyelitis and ameliorated inflammation in a delayed type hypersensitivity response model. In vitro, PDAC cells suppressed T-cell proliferation and inhibited Th1 and Th17 differentiation. Analysis of tissues derived from PDAC cell-treated animals revealed diminished CD86 expression on splenic DC, suggesting that they can also modulate DC populations. Furthermore, PDAC cells modulate the differentiation and maturation of mouse bone marrow-derived DC. Similarly, human DC differentiated from CD14(+) monocytes in the presence of PDAC cells acquired a tolerogenic phenotype. These tolerogenic DC failed to induce allogeneic T-cell proliferation and differentiation toward Th1, but skewed T-cell differentiation toward Th2. Inhibition of cyclo-oxygenase-2 activity resulted in a significant, but not complete, abrogation of PDAC cells' effects on DC phenotype and function, implying a role for prostaglandin E2 in PDAC-mediated immunomodulation. This study identifies modulation of DC differentiation toward immune tolerance as a key mechanism underlying the immunomodulatory activities of PDAC cells.
authors.affiliation: Celgene Cellular Therapeutics , Warren, NJ, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Celgene Cellular Therapeutics , Warren, NJ, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Morschauser
authors.affiliation: Celgene Cellular Therapeutics , Warren, NJ, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Celgene Cellular Therapeutics , Warren, NJ, USA.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Lu
authors.affiliation: Celgene Cellular Therapeutics , Warren, NJ, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Gleason
authors.affiliation: Celgene Cellular Therapeutics , Warren, NJ, USA.
authors.forename: Shuyang
authors.initials: S
authors.lastname: He
authors.affiliation: Celgene Cellular Therapeutics , Warren, NJ, USA.
authors.forename: Hong-Jung
authors.initials: HJ
authors.lastname: Chen
authors.affiliation: Celgene Cellular Therapeutics , Warren, NJ, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Jankovic
authors.affiliation: Celgene Cellular Therapeutics , Warren, NJ, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Ye
authors.affiliation: Celgene Cellular Therapeutics , Warren, NJ, USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Labazzo
authors.affiliation: Celgene Cellular Therapeutics , Warren, NJ, USA.
authors.forename: Uri
authors.initials: U
authors.lastname: Herzberg
authors.affiliation: Celgene Cellular Therapeutics , Warren, NJ, USA.
authors.forename: Vivian R
authors.initials: VR
authors.lastname: Albert
authors.affiliation: Celgene Cellular Therapeutics , Warren, NJ, USA.
authors.forename: Stewart E
authors.initials: SE
authors.lastname: Abbot
authors.affiliation: Celgene Cellular Therapeutics , Warren, NJ, USA.
authors.forename: Bitao
authors.initials: B
authors.lastname: Liang
authors.affiliation: Celgene Cellular Therapeutics , Warren, NJ, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Hariri
keywords: antigen presenting cells; dendritic cells; mesenchymal stromal/stem cell; placenta-derived adherent cells; prostaglandin E2; tolerogenic