Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli

Blood ◽  
2002 ◽  
Vol 99 (10) ◽  
pp. 3838-3843 ◽  
Author(s):  
Massimo Di Nicola ◽  
Carmelo Carlo-Stella ◽  
Michele Magni ◽  
Marco Milanesi ◽  
Paolo D. Longoni ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
T Lymphocyte ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Lymphocyte Proliferation ◽  
Marrow Stromal Cells ◽  
Soluble Factors ◽  
T Lymphocyte Proliferation

CD2+ T lymphocytes obtained from either the donor of bone marrow stromal cells (BMSCs) or a third party were cultured in mixed lymphocyte reactions (MLRs) with either allogeneic dendritic cells (DCs) or peripheral blood lymphocytes (PBLs). When autologous or allogeneic BMSCs were added back to T cells stimulated by DCs or PBLs, a significant and dose-dependent reduction of T-cell proliferation, ranging from 60% ± 5% to 98% ± 1%, was evident. Similarly, addition of BMSCs to T cells stimulated by polyclonal activators resulted in a 65% ± 5% (P = .0001) suppression of proliferation. BMSC- induced T-cell suppression was still evident when BMSCs were added in culture as late as 5 days after starting of MLRs. BMSC-inhibited T lymphocytes were not apoptotic and efficiently proliferated on restimulation. BMSCs significantly suppressed both CD4+ and CD8+ T cells (65% ± 5%, [P = .0005] and 75% ± 15% [P = .0005], respectively). Transwell experiments, in which cell-cell contact between BMSCs and effector cells was prevented, resulted in a significant inhibition of T-lymphocyte proliferation, suggesting that soluble factors were involved in this phenomenon. By using neutralizing monoclonal antibodies, transforming growth factor β1 and hepatocyte growth factor were identified as the mediators of BMSC effects. In conclusion, our data demonstrate that (1) autologous or allogeneic BMSCs strongly suppress T-lymphocyte proliferation, (2) this phenomenon that is triggered by both cellular as well as nonspecific mitogenic stimuli has no immunologic restriction, and (3) T-cell inhibition is not due to induction of apoptosis and is likely due to the production of soluble factors.

Anti-Myeloma Effects of γδ T Cells Are Hampered by Bone Marrow Stromal Cells but Resumed by Stromal Cell-Derived Osteoblasts.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1685-1685
Author(s):  
Kenichiro Yata ◽  
Masahiro Abe ◽  
Asuka Oda ◽  
Hiroe Amou ◽  
Masahiro Hiasa ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Critical Role ◽  
Cell Activity ◽  
Γδ T Cells ◽  
Marrow Stromal Cells ◽  
Γδ T Cell

Abstract Multiple myeloma (MM) remains incurable by conventional chemotherapies, leading to the idea to develop various forms of immunotherapies. γδ T cells are important effectors in the first-line defense against infections and tumors, and play a critical role in host defense and tumor surveillance. Aminobisphosphonates, a potent anti-resorptive agent, can effectively expand γδ T cells in vitro from peripheral blood mononuclear cells (PBMC) in combination with IL-2 in human; thus expanded γδ T cells have been demonstrated to exert potent anti-MM effects and draws considerable attention as a novel immunotherapeutic maneuver. However, in contrast to their in vitro anti-MM effects, their efficacy against MM cell growth in the bone marrow appears to be limited in patients with MM, although their clinical application is underway in MM. MM cells expands in a manner dependent on bone marrow microenvironment, in which stromal cells with defective osteoblast differentiation along with osteoclasts create a microenvironment suitable for MM cell growth and survival (a MM niche) to protect MM cells from various apoptotic insults. Because the effects of MM bone marrow microenvironment on γδ T cell activity is largely unknown, the present study was undertaken to clarify the roles of microenvironmental cells in MM bone marrow in cytotoxic activity of γδ T cells against MM cells. γδ T cells were substantially expanded (30- to 100-fold increase) when PBMC were stimulated with zoledronic acid and IL-2 for 1–2 weeks. When the γδ T cells were added exogenously to co-cultures of PBMC–derived OCs and MM cell lines (RPMI8226 and U266), γδ T cells adhered to OCs as well as MM cells and almost completely destroyed both of them, suggesting the susceptibility of OCs and MM cells to γδ T cells. Because such γδ T cell-mediated cytolysis is contact-dependent, we next explored the adhesion-mediated mechanisms. We found strong surface expression of DNAX accessory molecule-1 (DNAM-1; CD226) along with LFA-1 on γδ T cells, both of which are known as an adhesion molecule with signal transduction, and act as co-stimulatory molecules in cytotoxic T cells and NK cells. Blockade of either DNAM-1 or LFA-1 substantially reduced cytolysis of OCs as well as MM cells by γδ T cells, demonstrating their critical role as co-stimulatory molecules in γδ T cells. In contrast, the cytotoxic activity of γδ T cells against MM cells was potently attenuated in the presence of bone marrow stromal cells. Pretreatment of γδ T cells with stromal cells down-regulated interferon-γ production along with a decrease in DNAM-1 expression by γδ T cells. These results suggest that bone marrow stromal cells may be responsible for attenuation of anti-MM effects by γδT cells in vivo through directly blunting γδ T cell activity in addition to protection of MM cells from apoptosis. We and others have recently demonstrated that terminally differentiated osteblasts derived from stromal cells induce MM cell apoptosis. In contrast to stromal cells, terminally differentiated osteblasts allowed MM cell eradication by γδ T cells. Therefore, induction of terminally differentiation of osteblasts from stromal cells not only ameliorates bone lesions but also may disrupt a MM niche to confer susceptibility to γδ T cells in MM cells, which is hampered by bone marrow stromal cells.

Differentiation and Immunoregulatory Activity of Dental Pulp-Derived Mesenchymal Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4245-4245
Author(s):  
Alberto Grossi ◽  
Laura Pierdomenico ◽  
Laura Bonsi ◽  
Cosetta Marchionni ◽  
Francesco Alviano ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Lymphocyte ◽  
Dental Pulp ◽  
Lymphocyte Proliferation ◽  
Chondrogenic Differentiation ◽  
Flow Cytometric Analysis ◽  
Type Ii Collagen ◽  
Type Ii ◽  
T Lymphocyte Proliferation

Abstract INTRODUCTION. Mesenchymal Stem Cells (MSC) have the ability to renew and differentiate into various lineages of mesenchymal tissue such as bone, cartilage, fat, muscle, etc. Moreover they are not immunogenic and display immunoregulatory activity in preclinical animal models. The aim of this study was to investigate whether dental pulp MSC (DPMSC) were able to differentiate toward osteogenesis, chondrogenesis and adipogenesis and express the characteristic immunomodulatory activity of MSC derived from known sources such as bone marrow. METHODS and RESULTS. We isolated MSC from dental pulp and bone marrow samples obtained from fully informed healthy donors. Flow cytometric analysis showed that either DPMSC or bone marrow MSC (BMMSC) expressed the membrane antigens SH2, SH3, SH4, CD29 and CD166, while CD 14, CD 34 and CD 45 were negative. Cell differentiation was evaluated after PDMSC and BMMSC were cultured in appropriate conditions. To evaluate adipogenesis after 2–3 weeks of culture the cells, containing neutral lipids in fat vacuoles, were fixed in 10% formalin and stained with fresh oil red-O solution. To demonstrate osteogenic differentiation, the cultures were fixed and subjected to alkaline phosphatase and von Kossa staining. For chondrogenic differentiation pellets were formalin fixed, embedded in paraffin, examined morphologically and immunostained for Type II collagen. We observed that either PDMSC and BMMSC were able to express clear osteogenic and chondrogenic differentiation as demonstrated by von Kossa staining and Type II collagen immunostaining respectively, but a lower number of adipocytes was obtained, according to morphology and red-oil staining, in DPMSC cultures. For proliferation assay cells were incubated overnight, then [methyl-3H] Thymidine was added (Time 0) and radioactivity followed for up to 15 days. DPMSC and BMMSc presented a very different behaviour in that DPMSC radioactivity had a steep increase from day 3 to 8, then decreasing at day 15, although still above the baseline value. On the contrary BMMSC radioactivity did not change significantly over the time of observation. Modulation of T Lymphocyte proliferation was studied by coculturing PHA stimulated T cells in the presence of MSC. Compared to cultures of T cells alone, the uptake of [methyl-3H] Thymidine was inhibited by 75%±3%(BMMSC)or 91%±4% (DPMSC). CONCLUSIONS: Dental pulp is a source of cells expressing the typical phenotype of MSC. Compared to BMMSC, DPMSC present a higher rate of proliferating cells (S-phase), and lower differentiation capabilities toward adipogenesis. These results suggest that BMMSC and DPMSCs are present at diverse differentiation stages, possibly not evidenced by phenotypic characteristics, and their plasticity in different experimental conditions should be further investigated. DPMSC are able to suppress stimulated T lymphocyte proliferation, as described for BMMSC. Therefore they are good candidates when modulation of T cell activity is required, as shown recently by Le Blanc (2003) in the treatment of GVHD in allogeneic transplantation setting.

Bone Marrow Stromal Cells Act as Feeder Cells for Tendon Fibroblasts through Soluble Factors

2006 ◽  
Vol 0 (0) ◽  
pp. 061220075423013
Author(s):  
Kazumi Shimode ◽  
Norimasa Iwasaki ◽  
Tokifumi Majima ◽  
Tadanao Funakoshi ◽  
Naohiro Sawaguchi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Marrow Stromal Cells ◽  
Feeder Cells ◽  
Soluble Factors

CD40-ligand stimulates myelopoiesis by regulating flt3-ligand and thrombopoietin production in bone marrow stromal cells

Blood ◽  
2000 ◽  
Vol 95 (12) ◽  
pp. 3758-3764 ◽  
Author(s):  
Anne Solanilla ◽  
Julie Déchanet ◽  
Abdel El Andaloussi ◽  
Moryse Dupouy ◽  
François Godard ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Cell Activation ◽  
Cd40 Ligand ◽  
Marrow Stromal Cells ◽  
B Cell Activation ◽  
Noticeable Effect

Abstract CD40 ligand (CD40L)/CD40 interactions play a central role in T-cell–dependent B-cell activation as previously shown by in vitro studies, the phenotype of CD40L knockout mice and the defective expression of CD40L in patients who have X-linked immunodeficiency with hyper-IgM. The distribution of CD40 in cells other than of myeloid and lymphoid lineages has suggested additional functions for this receptor/ligand couple. Here we show that CD40L stimulates myelopoiesis with a noticeable effect on megakaryocytopoiesis in cocultures of hematopoietic progenitor cells and bone marrow stromal cells. These results suggest a mechanism by which T-cell or platelet-associated or soluble CD40L may regulate myelopoiesis.

Dependency of CLL Cell Survival on Direct Physical Interaction with Bone Marrow Stromal Cells In Vitro Is Largely Outweighed by Secretion of Soluble Factors with Time In Culture

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1365-1365 ◽  
Author(s):  
Iris Gehrke ◽  
Simon Jonas Poll-Wolbeck ◽  
Michael Hallek ◽  
Karl-Anton Kreuzer
Keyword(s):  
Bone Marrow ◽  
Cell Survival ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Culture Conditions ◽  
Marrow Stromal Cells ◽  
Physical Contact ◽  
Physical Interaction ◽  
Soluble Factors

Abstract Abstract 1365 The major pathophysiology feature of chronic lymphocytic leukemia (CLL) cells is their extended life span due to a pronounced resistance towards apoptotic stimuli in vivo. Despite this, CLL cells die within a few days when isolated from their natural microenvironment and are placed under cell culture conditions. That is why the bone marrow microenvironment has been ascribed an essential role in maintenance of the apoptotic resistance of the CLL cell. Thereby both, the physical interaction between bone marrow stromal cells and CLL cells and the secretion of soluble factors have been described to be essentially involved. We analysed the survival capacity of CLL cells in monoculture and in coculture with the bone marrow-derived stromal cell line HS5 with and without physical separation using transwells for up to 7 days by flow cytometric determination of Annexin-V/PI status. As expected, in vitro CLL cell survival was significantly reduced when physical contact between CLL cells and bone marrow stromal cells was prevented. Interestingly, this was only the case for short term cultivation for up to three days. With time under culture conditions CLL cell survival became less dependent on direct physical contact with the HS5 feederlayer, suggesting the secretion of soluble factors to compensate for the loss of pro-survival signals obtained from direct cell-cell interactions over time. This was further supported by the fact of reduced survival support for CLL cells when HS5 proliferation, hence production and secretion of soluble factors, was prevented by mitomycin treatment or formaldehyde fixation. The use of an expanded human Cytokine Antibody Array (Affymetrix), which analyses the presence of the most common 36 cytokine proteins, might offer information about the composition of soluble factors present in the supernatant which are essential for CLL cell survival in vitro. In conclusion, while direct cell-cell contact between CLL cells and bone marrow stromal cells provides an immediate protection against in vitro apoptosis of CLL cells, the secretion of soluble factors, most likely by both, CLL and bone marrow stormal cells, leads to the creation of an in vitro environment which can to a certain extent compensate for the loss of prosurvival signals obtained by direct physical interactions. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Human Regulatory T Cells Do Not Suppress the Antitumor Immunity in the Bone Marrow: A Role for Bone Marrow Stromal Cells in Neutralizing Regulatory T Cells

2013 ◽  
Vol 19 (6) ◽  
pp. 1467-1475 ◽  
Author(s):  
Teun Guichelaar ◽  
Maarten E. Emmelot ◽  
Henk Rozemuller ◽  
Bianka Martini ◽  
Richard W.J. Groen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Regulatory T Cells ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Antitumor Immunity ◽  
Marrow Stromal Cells

scholarly journals Immune targeting of fibroblast activation protein triggers recognition of multipotent bone marrow stromal cells and cachexia

2013 ◽  
Vol 210 (6) ◽  
pp. 1125-1135 ◽  
Author(s):  
Eric Tran ◽  
Dhanalakshmi Chinnasamy ◽  
Zhiya Yu ◽  
Richard A. Morgan ◽  
Chyi-Chia Richard Lee ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Fibroblast Activation Protein ◽  
Marrow Stromal Cells ◽  
Target Antigen ◽  
Antitumor Effects ◽  
Stromal Fibroblasts ◽  
Fibroblast Activation

Fibroblast activation protein (FAP) is a candidate universal target antigen because it has been reported to be selectively expressed in nearly all solid tumors by a subset of immunosuppressive tumor stromal fibroblasts. We verified that 18/18 human tumors of various histologies contained pronounced stromal elements staining strongly for FAP, and hypothesized that targeting tumor stroma with FAP-reactive T cells would inhibit tumor growth in cancer-bearing hosts. T cells genetically engineered with FAP-reactive chimeric antigen receptors (CARs) specifically degranulated and produced effector cytokines upon stimulation with FAP or FAP-expressing cell lines. However, adoptive transfer of FAP-reactive T cells into mice bearing a variety of subcutaneous tumors mediated limited antitumor effects and induced significant cachexia and lethal bone toxicities in two mouse strains. We found that FAP was robustly expressed on PDGFR-α+, Sca-1+ multipotent bone marrow stromal cells (BMSCs) in mice, as well as on well-characterized, clinical-grade multipotent human BMSCs. Accordingly, both mouse and human multipotent BMSCs were recognized by FAP-reactive T cells. The lethal bone toxicity and cachexia observed after cell-based immunotherapy targeting FAP cautions against its use as a universal target. Moreover, the expression of FAP by multipotent BMSCs may point toward the cellular origins of tumor stromal fibroblasts.

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