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Immunoregulation by mesenchymal stem cells: biological aspects and clinical applications.

Castro-Manrreza ME, Montesinos JJ - J Immunol Res (2015)

Bottom Line: Mesenchymal stem cells (MSCs) are multipotent cells capable of differentiation into mesenchymal lineages and that can be isolated from various tissues and easily cultivated in vitro.Currently, MSCs are of considerable interest because of the biological characteristics that confer high potential applicability in the clinical treatment of many diseases.In this review, we discuss the current knowledge about the capacity of MSCs for the immunoregulation of immunocompetent cells and emphasize the effects of MSCs on T cells, principal effectors of the immune response, and the immunosuppressive effects mediated by the secretion of soluble factors and membrane molecules.

View Article: PubMed Central - PubMed

Affiliation: Mesenchymal Stem Cells Laboratory, Oncology Research Unit, Oncology Hospital, National Medical Center, IMSS, Avenue Cuauhtémoc 330 Col. Doctores, 06720 Mexico City, DF, Mexico.

ABSTRACT
Mesenchymal stem cells (MSCs) are multipotent cells capable of differentiation into mesenchymal lineages and that can be isolated from various tissues and easily cultivated in vitro. Currently, MSCs are of considerable interest because of the biological characteristics that confer high potential applicability in the clinical treatment of many diseases. Specifically, because of their high immunoregulatory capacity, MSCs are used as tools in cellular therapies for clinical protocols involving immune system alterations. In this review, we discuss the current knowledge about the capacity of MSCs for the immunoregulation of immunocompetent cells and emphasize the effects of MSCs on T cells, principal effectors of the immune response, and the immunosuppressive effects mediated by the secretion of soluble factors and membrane molecules. We also describe the mechanisms of MSC immunoregulatory modulation and the participation of MSCs as immune response regulators in several autoimmune diseases, and we emphasize the clinical application in graft versus host disease (GVHD).

No MeSH data available.


Related in: MedlinePlus

Immunoregulatory effect of MSCs on T lymphocytes. MSCs can induce the sustained expression of CTLA-4 and CD69 activation molecules on T cells, which have been related with generation of cells with immunoregulatory properties. Cell-to-cell contact seems to be required for the increase of CTLA-4 expression. Dependent and independent mechanisms of cellular contact are involved in the decrease of proliferation of CD4+ and CD8+ T cells and in generation of Foxp3+ Tregs by MSCs. Cytokines such as IL-10 can stimulate the expression and secretion of HLA-G5 by MSCs and in turn it stimulates the secretion of IL-10 in a positive feedback loop. The initial contact between MSCs and T lymphocytes seems to be required for initiation of the feedback loop. PGE2 secreted by MSCs is involved in generation of Tr1 cells. HLA-G5 supports differentiation of Th2 cells and IDO decrease differentiation of Th17.
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fig1: Immunoregulatory effect of MSCs on T lymphocytes. MSCs can induce the sustained expression of CTLA-4 and CD69 activation molecules on T cells, which have been related with generation of cells with immunoregulatory properties. Cell-to-cell contact seems to be required for the increase of CTLA-4 expression. Dependent and independent mechanisms of cellular contact are involved in the decrease of proliferation of CD4+ and CD8+ T cells and in generation of Foxp3+ Tregs by MSCs. Cytokines such as IL-10 can stimulate the expression and secretion of HLA-G5 by MSCs and in turn it stimulates the secretion of IL-10 in a positive feedback loop. The initial contact between MSCs and T lymphocytes seems to be required for initiation of the feedback loop. PGE2 secreted by MSCs is involved in generation of Tr1 cells. HLA-G5 supports differentiation of Th2 cells and IDO decrease differentiation of Th17.

Mentions: (2) Proliferation. The effect of MSCs on the proliferation of T lymphocytes is independent of the activation method. The first studies to analyze the effects of BM-MSCs on the proliferation of T lymphocytes used irradiated MSCs that were cocultivated with alloantigen-stimulated PBMC. These studies reported that MSCs inhibited T-cell proliferation in a dose-dependent fashion [13, 16, 17, 19]. However, in addition to inhibiting alloantigen-induced proliferation, MSCs can inhibit proliferation induced by polyclonal activators such as PHA [14, 26] or anti-CD3/CD28 [21, 23, 24]. The immunosuppressive effects of MSCs have been analyzed using total populations of PBMC and populations enriched in CD3+, CD4+, or CD8+ lymphocytes. Every case has demonstrated the capacity of MSCs to diminish proliferation [13, 16, 17, 19, 21, 23, 24]. Immunoregulation has been shown to be independent of the induction of apoptosis [16, 27] and is performed through mechanisms dependent and independent of cellular contact. Among the secreted factors identified are transforming growth factor beta 1 (TGFβ1), hepatocyte growth factor (HGF), indoleamine-2,3-dioxygenase (IDO), prostaglandin E2 (PGE2), IL-10, and HLA-G5 [13, 17, 28], whereas programmed death-ligand 1 (PD-L1) and HLA-G1 are involved in contact-dependent mechanisms (Figure 1) [28–30]. Whether direct contact between MSCs and T lymphocytes is necessary for the inhibition of T-cell proliferation remains controversial. Some authors have suggested that MSCs act via an immunosuppressive mechanism independent of cell-to-cell contact [31, 32], whereas others have indicated that contact is required for efficient immunoregulation [24, 28–30, 33, 34]. However, the mechanism of MSC immunoregulation appears to depend on cellular populations, mode of activation, and the presence or absence of cell-to-cell contact [23, 32].


Immunoregulation by mesenchymal stem cells: biological aspects and clinical applications.

Castro-Manrreza ME, Montesinos JJ - J Immunol Res (2015)

Immunoregulatory effect of MSCs on T lymphocytes. MSCs can induce the sustained expression of CTLA-4 and CD69 activation molecules on T cells, which have been related with generation of cells with immunoregulatory properties. Cell-to-cell contact seems to be required for the increase of CTLA-4 expression. Dependent and independent mechanisms of cellular contact are involved in the decrease of proliferation of CD4+ and CD8+ T cells and in generation of Foxp3+ Tregs by MSCs. Cytokines such as IL-10 can stimulate the expression and secretion of HLA-G5 by MSCs and in turn it stimulates the secretion of IL-10 in a positive feedback loop. The initial contact between MSCs and T lymphocytes seems to be required for initiation of the feedback loop. PGE2 secreted by MSCs is involved in generation of Tr1 cells. HLA-G5 supports differentiation of Th2 cells and IDO decrease differentiation of Th17.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4417567&req=5

fig1: Immunoregulatory effect of MSCs on T lymphocytes. MSCs can induce the sustained expression of CTLA-4 and CD69 activation molecules on T cells, which have been related with generation of cells with immunoregulatory properties. Cell-to-cell contact seems to be required for the increase of CTLA-4 expression. Dependent and independent mechanisms of cellular contact are involved in the decrease of proliferation of CD4+ and CD8+ T cells and in generation of Foxp3+ Tregs by MSCs. Cytokines such as IL-10 can stimulate the expression and secretion of HLA-G5 by MSCs and in turn it stimulates the secretion of IL-10 in a positive feedback loop. The initial contact between MSCs and T lymphocytes seems to be required for initiation of the feedback loop. PGE2 secreted by MSCs is involved in generation of Tr1 cells. HLA-G5 supports differentiation of Th2 cells and IDO decrease differentiation of Th17.
Mentions: (2) Proliferation. The effect of MSCs on the proliferation of T lymphocytes is independent of the activation method. The first studies to analyze the effects of BM-MSCs on the proliferation of T lymphocytes used irradiated MSCs that were cocultivated with alloantigen-stimulated PBMC. These studies reported that MSCs inhibited T-cell proliferation in a dose-dependent fashion [13, 16, 17, 19]. However, in addition to inhibiting alloantigen-induced proliferation, MSCs can inhibit proliferation induced by polyclonal activators such as PHA [14, 26] or anti-CD3/CD28 [21, 23, 24]. The immunosuppressive effects of MSCs have been analyzed using total populations of PBMC and populations enriched in CD3+, CD4+, or CD8+ lymphocytes. Every case has demonstrated the capacity of MSCs to diminish proliferation [13, 16, 17, 19, 21, 23, 24]. Immunoregulation has been shown to be independent of the induction of apoptosis [16, 27] and is performed through mechanisms dependent and independent of cellular contact. Among the secreted factors identified are transforming growth factor beta 1 (TGFβ1), hepatocyte growth factor (HGF), indoleamine-2,3-dioxygenase (IDO), prostaglandin E2 (PGE2), IL-10, and HLA-G5 [13, 17, 28], whereas programmed death-ligand 1 (PD-L1) and HLA-G1 are involved in contact-dependent mechanisms (Figure 1) [28–30]. Whether direct contact between MSCs and T lymphocytes is necessary for the inhibition of T-cell proliferation remains controversial. Some authors have suggested that MSCs act via an immunosuppressive mechanism independent of cell-to-cell contact [31, 32], whereas others have indicated that contact is required for efficient immunoregulation [24, 28–30, 33, 34]. However, the mechanism of MSC immunoregulation appears to depend on cellular populations, mode of activation, and the presence or absence of cell-to-cell contact [23, 32].

Bottom Line: Mesenchymal stem cells (MSCs) are multipotent cells capable of differentiation into mesenchymal lineages and that can be isolated from various tissues and easily cultivated in vitro.Currently, MSCs are of considerable interest because of the biological characteristics that confer high potential applicability in the clinical treatment of many diseases.In this review, we discuss the current knowledge about the capacity of MSCs for the immunoregulation of immunocompetent cells and emphasize the effects of MSCs on T cells, principal effectors of the immune response, and the immunosuppressive effects mediated by the secretion of soluble factors and membrane molecules.

View Article: PubMed Central - PubMed

Affiliation: Mesenchymal Stem Cells Laboratory, Oncology Research Unit, Oncology Hospital, National Medical Center, IMSS, Avenue Cuauhtémoc 330 Col. Doctores, 06720 Mexico City, DF, Mexico.

ABSTRACT
Mesenchymal stem cells (MSCs) are multipotent cells capable of differentiation into mesenchymal lineages and that can be isolated from various tissues and easily cultivated in vitro. Currently, MSCs are of considerable interest because of the biological characteristics that confer high potential applicability in the clinical treatment of many diseases. Specifically, because of their high immunoregulatory capacity, MSCs are used as tools in cellular therapies for clinical protocols involving immune system alterations. In this review, we discuss the current knowledge about the capacity of MSCs for the immunoregulation of immunocompetent cells and emphasize the effects of MSCs on T cells, principal effectors of the immune response, and the immunosuppressive effects mediated by the secretion of soluble factors and membrane molecules. We also describe the mechanisms of MSC immunoregulatory modulation and the participation of MSCs as immune response regulators in several autoimmune diseases, and we emphasize the clinical application in graft versus host disease (GVHD).

No MeSH data available.


Related in: MedlinePlus