Mesenchymal Stem Cells for Treatment and Prevention of Graft-Versus-Host Disease After Allogeneic Hematopoietic Cell Transplantation

Blood and Marrow Transplantation Program, Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA.
Current Stem Cell Research & Therapy (Impact Factor: 2.21). 01/2010; 4(4):252-9. DOI: 10.2174/157488809789649269
Source: PubMed


Allogeneic hematopoietic cell transplantation (allo-HCT) is an effective therapy for hematological malignancies and inherited diseases. However, acute graft-versus-host-disease (aGVHD) is a major life-threatening complication after allo-HCT and there are few therapeutic options for severe steroid-refractory aGVHD. Preliminary studies on co-transplantation of mesenchymal stem cells (MSCs) have shown an improvement in or resolution of severe aGVHD. However, the mechanism underlying this immunosuppressive effect has not been elucidated. Most of the data suggest that the immunosuppressive effect involves soluble factors such as IL-6 or TGF-beta as well as cell-cell contact dependence. MSCs interact either directly with T cells or indirectly via other immune cells such as dendritic cells and NK cells. Here we review the immunomodulatory function of MSCs in allo-HCT and their potential usefulness in the treatment or prevention of severe acute GVHD.

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    • "They have immunosuppressive properties [7] and are regarded as non-immunogenic [8], two qualities which are highly desirable for transplantation into an allogeneic host. MSCs have been widely used in bone marrow transplantation [9], tissue engineering [10], and cell therapy [11]. "
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    ABSTRACT: Mesenchymal stem cells (MSCs) are non-immunogenic, multipotent cells with at least trilineage differentiation potential. They promote wound healing, improve regeneration of injured tissue, and mediate numerous other health effects. MSCs migrate to sites of injury and stimulate repair either through direct differentiation or indirectly through the stimulation of endogenous repair mechanisms. Using the in vitro scratch assay, we show that the inflammatory cytokines, chemokines, and growth factors TNF-α, SDF-1, PDGF, and bFGF enhance migration of rat MSCs under normoxic conditions, while TNF-α, IFN-γ, PDGF, and bFGF promote MSC migration under hypoxic conditions. This indicates that the oxygen concentration affects how MSCs will migrate in response to specific factors and, consistent with this, differential expression of cytokines was observed under hypoxic versus normoxic conditions. Using the transwell migration assay, we find that TNF-α, IFN-γ, bFGF, IGF-1, PDGF, and SDF-1 significantly increase transmigration of rat MSCs compared to unstimulated medium. MSCs derived from aged rats exhibited comparable migration to MSCs derived from young rats under hypoxic and normoxic conditions, even after application with specific factors. Similarly, migration in MSCs from aged, human donors did not statistically differ compared to migration in MSCs derived from human umbilical cord tissue or younger donors. Copyright © 2015. Published by Elsevier Inc.
    Experimental Cell Research 09/2015; 338(1). DOI:10.1016/j.yexcr.2015.08.019 · 3.25 Impact Factor
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    • "The above mentioned and/or other mechanisms can change the inflammatory environment to immune tolerant. It looks suitable the use of the immunosuppressive activity of MSC to the treatment of autoimmune diseases [14] [15] as well as of graft-versus-host-disease (GVHD), an important complication after allogeneic hematopoietic cells transplantation [16]. GVHD is "
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    ABSTRACT: Mesenchymal stromal cells (MSC) are fibroblast-like cells present in different types of tissues. Their immunomodulatory potential represents a promising method for post-transplant immunotherapy in the treatment of GVHD (graft-versus-host disease) with suboptimal response to standard immunosuppression. In this study we tested influence of 1–8 month-long cryopreservation on ability of MSC to suppress activation of non-specifically stimulated lymphocytes. We did not observe any changes in proliferation capacity of MSC after thawing. Lymphocytes metabolic activity was inhibited by 30% and number of dividing cells was three times smaller in the presence of MSC. Two activation markers were studied (CD25 and CD69) to confirm preservation of functional cell integrity. Expression of CD25 antigen on CD3+CD4+ and CD3+CD4− cells was decreased in all co-cultivated samples. Level of CD69 expression on CD3+CD4+ cells was lower in samples with added MSC (10–15% on day +2) but without reaching statistical significance. The lower expression (approximately 5%) was observed also on CD4-cells. The study confirms the preservation of immunomodulatory properties of cryopreserved and re-expanded MSC. Aliquots with cryopreserved cells can represent an optimal source for a quick preparation of MSC cell product with the possibility to apply the same cells repeatedly.
    Biologicals 05/2014; 42(3). DOI:10.1016/j.biologicals.2014.01.003 · 1.21 Impact Factor
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    • "Due to their immunosuppressive activities, hMSCs have been used in many investigational clinical trials to investigate their potential to treat immunological disorders or inflammation-mediated pathological lesions, including Crohn’s disease, T1D and GVHD (reviewed in [16]). They have also been investigated in co-transfer experiments intended to improve the engraftment of allogeneic pancreatic islet transplant [31] and hematopoietic stem cells [32,33]. Because of the heterogeneous nature of hMSCs, the establishment of quantitative bioassays that could detect differences between hMSCs from different donors and passages would potentially be of great value for manufacturing and MSC product assessment purposes. "
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    ABSTRACT: Mesenchymal stem cells (MSCs) have immunosuppressive activity. They do not induce allospecific T cell responses, making them promising tools for reducing the severity of graft versus host disease (GVHD) as well as treating various immune diseases. Currently, there is a need in the MSC field to develop a robust in vitro bioassay which can characterize the immunosuppressive function of MSCs. Murine clonal CD4 and CD8 T cells were stimulated with cognate peptide antigen and antigen presenting cells (APCs) in the absence or presence of human MSCs, different aspects of T cell activation were monitored and analyzed using flow cytometery, real time RT-PCR and cytokine measurement. Human MSCs (hMSCs) can alter multiple aspects of murine T cell activation induced by stimulation with specific antigen, including: reduced proliferation, inhibited or stimulated cell surface marker expression (CD25, CD69, CD44 and CD62L), inhibited mRNA expression of transcription factors (T-bet and GATA-3) and decreased cytokine expression (interferon-gamma, interleukin-10). Disappearance of activation-induced cluster formation and decreased apoptosis of CD8 T cells were also observed. Moreover, the effects are specific to MSCs; incubating the T cells with non-MSC control cell lines had no effect on T cell proliferation and activation. Clonal murine T cells can be used to measure, characterize, and quantify the in vitro immunosuppressive activity of human MSCs, representing a promising approach to improve bioassays for immunosuppression.
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