Human placenta-derived adherent cells induce tolerogenic immune responses.
Bottom Line: 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.
Affiliation: Celgene Cellular Therapeutics , Warren, NJ, USA.
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.
No MeSH data available.
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Mentions: The effects of PDAC cells on DC differentiation were further examined using human DC. Immature DC (iDC) were differentiated from human peripheral CD14+ monocytes in medium containing GM-CSF and IL-4, and cultured in the presence or absence of PDAC cells or PDAC-CM. iDC were then activated to develop into mature DC (mDC) by subsequent stimulation with LPS and IFN-γ. DC differentiation, indicated by the upregulation of DC markers and costimulatory molecules and downregulation of monocyte markers, was inhibited in the presence of PDAC cells. PDAC cells (Supplementary Online Figure 5a) or PDAC-CM (Figure 4a) reduced conventional DC (cDC) marker CD1a expression and enhanced expression of the plasmacytoid DC (pDC) marker CD123 and the monocyte lineage marker CD14 on iDC in a dose-dependent manner. DC differentiated in the presence of PDAC cells (PDAC-iDC) (Supplementary Online Figure 5a) or PDAC-CM also demonstrated dose-dependent reduction of costimulatory molecule CD86 expression and enhancement of PD-L1 expression (Figure 4a). Mature DC that were originally differentiated in the presence of PDAC cells or PDAC-CM (PDAC-mDC) were further impaired in their ability to express CD86 and induce the human DC maturation marker CD83, in response to LPS and IFN-γ stimulation (Supplementary Online Figure 5b and Figure 4b). Moreover, intracellular staining revealed reduced production of the Th1-polarizing cytokine IL-12 (Supplementary Online Figure 5b and Figure 4b). Secretory IL-12 and IL-23 production was also reduced along with an increase in IL-10 production in the culture supernatant of PDAC-mDC induced from PDAC-iDC that were originally differentiated in the presence of PDAC cells (Supplementary Online Figure 5c) or PDAC-CM (Figure 4c). Taken together, these findings suggest that PDAC cells can influence human MoDC differentiation toward a tolerogenic phenotype.
No MeSH data available.