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Human placenta-derived adherent cells induce tolerogenic immune responses.

Liu W, Morschauser A, Zhang X, Lu X, Gleason J, He S, Chen HJ, Jankovic V, Ye Q, Labazzo K, Herzberg U, Albert VR, Abbot SE, Liang B, Hariri R - Clin Transl Immunology (2014)

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.

View Article: PubMed Central - PubMed

Affiliation: Celgene Cellular Therapeutics , Warren, NJ, USA.

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.

No MeSH data available.


Related in: MedlinePlus

PDAC cells demonstrate immunoregulatory effects in vivo in three animal models. (a, b) OT-II Adoptive Transfer Model. PDAC cells at doses indicated and OT-II CD4+ T cells (3.36 × 106) were coadministered into recipient mice. Following OVA peptide stimulation, spleens were isolated for analysis of (a) proliferation index and (b) percentage of IL-10-producing OT-II CD4+ T cells. M, million cells. (c, d) DTH Model. Mice received PDAC cells or vehicle, as indicated, along with sRBC via separate tail veins. Mice were challenged with sRBC 4 days later by local injection with sRBC into the right paw. (c) Paw thickness, 24 h post challenge, expressed as the difference between right (sRBC challenged) and left paw. (d) Frequency of CD86+ cells in CD11c+ splenocytes. (e, f) EAE model. Nine days after immunization with MOG peptide, at the onset of EAE symptoms, mice received the treatments indicated. PDAC cells (1.5 × 106), vehicle and PBS were administered by tail vein injection; FTY720 was administered orally at 10 mg kg−1. (e) Clinical scores, evaluated daily. The data are expressed as the mean±s.e.m. of 10 mice per group. Mice received control FTY20 daily. In contrast, only a single dose of PDAC cells (arrow) was administered. (f) The frequency of Th17 cells (left) and IL-10-producing CD4+-infiltrating T cells (right) in the spinal cord isolated from EAE mice, measured by flow cytometry. Results are expressed as mean±s.e.m. of the percentage positive cells or proliferation index. Unless otherwise indicated, statistical significance for all parameters is denoted as *P<0.05, **P<0.01, ****P<0.0001, compared with appropriate vehicle control.
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fig2: PDAC cells demonstrate immunoregulatory effects in vivo in three animal models. (a, b) OT-II Adoptive Transfer Model. PDAC cells at doses indicated and OT-II CD4+ T cells (3.36 × 106) were coadministered into recipient mice. Following OVA peptide stimulation, spleens were isolated for analysis of (a) proliferation index and (b) percentage of IL-10-producing OT-II CD4+ T cells. M, million cells. (c, d) DTH Model. Mice received PDAC cells or vehicle, as indicated, along with sRBC via separate tail veins. Mice were challenged with sRBC 4 days later by local injection with sRBC into the right paw. (c) Paw thickness, 24 h post challenge, expressed as the difference between right (sRBC challenged) and left paw. (d) Frequency of CD86+ cells in CD11c+ splenocytes. (e, f) EAE model. Nine days after immunization with MOG peptide, at the onset of EAE symptoms, mice received the treatments indicated. PDAC cells (1.5 × 106), vehicle and PBS were administered by tail vein injection; FTY720 was administered orally at 10 mg kg−1. (e) Clinical scores, evaluated daily. The data are expressed as the mean±s.e.m. of 10 mice per group. Mice received control FTY20 daily. In contrast, only a single dose of PDAC cells (arrow) was administered. (f) The frequency of Th17 cells (left) and IL-10-producing CD4+-infiltrating T cells (right) in the spinal cord isolated from EAE mice, measured by flow cytometry. Results are expressed as mean±s.e.m. of the percentage positive cells or proliferation index. Unless otherwise indicated, statistical significance for all parameters is denoted as *P<0.05, **P<0.01, ****P<0.0001, compared with appropriate vehicle control.

Mentions: Animal models of T-cell-mediated inflammation were used to determine whether PDAC cells could induce a tolerogenic response in vivo. In the first example, an OT-II transgenic mouse model, expressing the T-cell receptor specific for ovalbumin (OVA), was used to evaluate the effects of PDAC cells on antigen-specific CD4+ T-cell proliferation. PDAC cells at doses of 0.3, 0.75 and 1.5 × 106 cells or vehicle were administered along with the adoptive transfer of CD4+ T cells isolated from OT-II mice into recipient wild-type mice following OVA peptide immunization. No effects on animal body weight or toxicities were observed following PDAC cell treatment (data not shown), but PDAC cell treatment led to a dose-dependent decrease in the OVA-specific CD4+ T-cell proliferative response in the spleen, as compared with vehicle-treated mice (Figure 2a). Coadministration of PDAC cells also resulted in an increase in the percentage of IL-10-producing splenic CD4+ T cells in a dose-dependent manner (Figure 2b), indicating an induction of tolerogenic T-cell populations in vivo.


Human placenta-derived adherent cells induce tolerogenic immune responses.

Liu W, Morschauser A, Zhang X, Lu X, Gleason J, He S, Chen HJ, Jankovic V, Ye Q, Labazzo K, Herzberg U, Albert VR, Abbot SE, Liang B, Hariri R - Clin Transl Immunology (2014)

PDAC cells demonstrate immunoregulatory effects in vivo in three animal models. (a, b) OT-II Adoptive Transfer Model. PDAC cells at doses indicated and OT-II CD4+ T cells (3.36 × 106) were coadministered into recipient mice. Following OVA peptide stimulation, spleens were isolated for analysis of (a) proliferation index and (b) percentage of IL-10-producing OT-II CD4+ T cells. M, million cells. (c, d) DTH Model. Mice received PDAC cells or vehicle, as indicated, along with sRBC via separate tail veins. Mice were challenged with sRBC 4 days later by local injection with sRBC into the right paw. (c) Paw thickness, 24 h post challenge, expressed as the difference between right (sRBC challenged) and left paw. (d) Frequency of CD86+ cells in CD11c+ splenocytes. (e, f) EAE model. Nine days after immunization with MOG peptide, at the onset of EAE symptoms, mice received the treatments indicated. PDAC cells (1.5 × 106), vehicle and PBS were administered by tail vein injection; FTY720 was administered orally at 10 mg kg−1. (e) Clinical scores, evaluated daily. The data are expressed as the mean±s.e.m. of 10 mice per group. Mice received control FTY20 daily. In contrast, only a single dose of PDAC cells (arrow) was administered. (f) The frequency of Th17 cells (left) and IL-10-producing CD4+-infiltrating T cells (right) in the spinal cord isolated from EAE mice, measured by flow cytometry. Results are expressed as mean±s.e.m. of the percentage positive cells or proliferation index. Unless otherwise indicated, statistical significance for all parameters is denoted as *P<0.05, **P<0.01, ****P<0.0001, compared with appropriate vehicle control.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4232071&req=5

fig2: PDAC cells demonstrate immunoregulatory effects in vivo in three animal models. (a, b) OT-II Adoptive Transfer Model. PDAC cells at doses indicated and OT-II CD4+ T cells (3.36 × 106) were coadministered into recipient mice. Following OVA peptide stimulation, spleens were isolated for analysis of (a) proliferation index and (b) percentage of IL-10-producing OT-II CD4+ T cells. M, million cells. (c, d) DTH Model. Mice received PDAC cells or vehicle, as indicated, along with sRBC via separate tail veins. Mice were challenged with sRBC 4 days later by local injection with sRBC into the right paw. (c) Paw thickness, 24 h post challenge, expressed as the difference between right (sRBC challenged) and left paw. (d) Frequency of CD86+ cells in CD11c+ splenocytes. (e, f) EAE model. Nine days after immunization with MOG peptide, at the onset of EAE symptoms, mice received the treatments indicated. PDAC cells (1.5 × 106), vehicle and PBS were administered by tail vein injection; FTY720 was administered orally at 10 mg kg−1. (e) Clinical scores, evaluated daily. The data are expressed as the mean±s.e.m. of 10 mice per group. Mice received control FTY20 daily. In contrast, only a single dose of PDAC cells (arrow) was administered. (f) The frequency of Th17 cells (left) and IL-10-producing CD4+-infiltrating T cells (right) in the spinal cord isolated from EAE mice, measured by flow cytometry. Results are expressed as mean±s.e.m. of the percentage positive cells or proliferation index. Unless otherwise indicated, statistical significance for all parameters is denoted as *P<0.05, **P<0.01, ****P<0.0001, compared with appropriate vehicle control.
Mentions: Animal models of T-cell-mediated inflammation were used to determine whether PDAC cells could induce a tolerogenic response in vivo. In the first example, an OT-II transgenic mouse model, expressing the T-cell receptor specific for ovalbumin (OVA), was used to evaluate the effects of PDAC cells on antigen-specific CD4+ T-cell proliferation. PDAC cells at doses of 0.3, 0.75 and 1.5 × 106 cells or vehicle were administered along with the adoptive transfer of CD4+ T cells isolated from OT-II mice into recipient wild-type mice following OVA peptide immunization. No effects on animal body weight or toxicities were observed following PDAC cell treatment (data not shown), but PDAC cell treatment led to a dose-dependent decrease in the OVA-specific CD4+ T-cell proliferative response in the spleen, as compared with vehicle-treated mice (Figure 2a). Coadministration of PDAC cells also resulted in an increase in the percentage of IL-10-producing splenic CD4+ T cells in a dose-dependent manner (Figure 2b), indicating an induction of tolerogenic T-cell populations in vivo.

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.

View Article: PubMed Central - PubMed

Affiliation: Celgene Cellular Therapeutics , Warren, NJ, USA.

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.

No MeSH data available.


Related in: MedlinePlus