Mesenchymal stem cells for treatment of severe acute graft-versus-host disease

Ringdén, Olle; Uzunel, Mehmet; Rasmusson, Ida; Remberger, Mats; Sundberg, Berit; Lönnies, Helena; Marschall, Hanns‐Ulrich; Dlugosz, Aldona; Szakos, Attila; Hassan, Zuzana; Omazic, Brigitta; Aschan, J; Barkholt, Lisbeth; Blanc, Katarina Le

doi:10.1016/j.bbmt.2005.11.015

Cited by 104 publications

(153 citation statements)

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“…Using cells isolated in this manner, we observed that MSC significantly reduced the mortality of GVHD as evidenced by survival data and supportive histological analyses. These data correlate to findings reported in clinical studies [22,24,47]. MSC had no significant efficacy when given at the time of transplant, on day 0, but significantly improved GVHD mortality when given during ongoing GVHD, on day 20.…”

Section: Discussionsupporting

confidence: 87%

IFN‐γ activation of mesenchymal stem cells for treatment and prevention of graft versus host disease

et al. 2008

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Graft versus host disease (GVHD), mediated by donor T cells, is a significant source of morbidity and mortality following allogeneic stem cell transplantation. Mesenchymal stem cells (MSC) can successfully treat ongoing graft versus host disease, presumably due to their ability to suppress donor T cell proliferation. Little is known about the potential of MSC to prevent GVHD. Here we show that bone marrow-isolated MSC can suppress the development of GVHD if given after donor T cell recognition of antigen. IFN-c was required to initiate MSC efficacy. Recipients of IFN-c -/-T cells did not respond to MSC treatment and succumbed to GVHD. MSC, pre-treated with IFN-c, became immediately active and could suppress GVHD more efficiently than a fivefold-greater number of MSC that were not activated. When given at the time of bone marrow transplantation, activated MSC could prevent GVHD mortality (100% survival, p=0.006). MSC activation was dependent on the magnitude of IFN-c exposure, with increased IFN-c exposure leading to increased MSC suppression of GVHD. Activated MSC present a new strategy for preventing GVHD using fewer MSC. Key words: Mesenchymal stem cell Á GVH disease Á IFN-c See accompanying commentary by Dazzi and Marelli-Berg IntroductionAllogeneic hematopoietic stem cell transplants have the potential to play a significant curative role in the treatment of malignant and non-malignant hematopoietic disorders, autoimmune diseases, and immunological deficiencies, and in the induction of transplantation tolerance [1][2][3][4][5][6][7][8][9][10]. Widespread application of this therapeutic modality is limited due to the morbidity and mortality of graft versus host disease (GVHD), which affects 50% of stem cell transplant recipients [11][12][13][14][15][16]. While grafts highly matched to the recipient, young donors, donor/recipient sex match, and posttransplant immunosuppression are strategies used to reduce the risk of GVHD [17], thus far, the greatest preventative measure has been intentional underutilization of stem cell transplantation. Theoretically, strategies aimed at preventing GVHD would target early initiating factors either during the inflammatory milieu created in the wake of tissue damage from conditioning regimens [18,19] or during T cell antigen recognition and proliferation [20,21]. Once the efferent effector phase occurs, donor T cell-mediated destruction of host tissues occurs and preventive strategies are replaced with treatment regimens [19].Mesenchymal stem cells (MSC) have been used in the efferent phase of GVHD to successfully treat ongoing, acute, steroidresistant GVHD [22,23]. In contrast, when given at the time of BM transplant, for the prevention of GVHD, the incidence of grade III/ IV GVHD was not significantly improved [24], suggesting the [26,27,29,30]. In addition, MSC do not suppress the modest T cell proliferative response to recall antigens [31]. These findings suggest MSC may exert their optimal effects during the events surrounding larger scale T cell activation and proliferat...

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Section: Discussionsupporting

confidence: 87%

IFN‐γ activation of mesenchymal stem cells for treatment and prevention of graft versus host disease

et al. 2008

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“…The immunological characteristics of BM-derived MSCs are another reason for the interest in the use of these cells for clinical applications [13][14][15][16]. Indeed, the use of third party ex vivo expanded HLA-mismatched MSCs in immune-dysregulation disorders such as graft versus host disease after allogeneic HSC transplantation and Crohn's disease have generated encouraging results, and are currently into phase-III trials [42][43][44].…”

Section: Discussionmentioning

confidence: 99%

Derivation and immunological characterization of mesenchymal stromal cells from human embryonic stem cells

Trivedi

Hematti

2008

Experimental Hematology

178

159

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Objective-We have previously shown the simultaneous generation of CD73+ mesenchymal stromal cells (MSCs) along with CD34+ hematopoietic cells from human embryonic stem cells (ESCs) when they are co-cultured with OP9 murine stromal cells. We investigated whether MSCs can be derived from human ESCs without co-culturing with OP9 cells, and if such cells exhibit immunological properties similar to MSCs derived from adult human bone marrow (BM).Materials and Methods-Our starting populations were undifferentiated ESCs cultured on matrigel-coated plates without feeder cells. The differentiated fibroblast-looking cells were tested for expression of MSC markers and their potential for multi-lineage differentiation. We investigated surface expression of HLA molecules on these MSCs before and after treatment with interferon gamma (IFN-γ). We also tested the proliferative response of T-lymphocytes towards MSCs and the effects of MSCs in mixed lymphocyte reaction (MLR) assays. Conclusions-MSCs can be derived from human ESCs without feeder cells. These human ESCderived MSCs have cell surface markers, differentiation potentials, and immunological properties in vitro that are similar to adult BM-derived MSCs. Results-We

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“…Furthermore, application of MSC is thought to enhance hematopoietic stem cell engraftment in the course of bone marrow transplantation , to correct inherited disorders of bone and cartilage (Bolland et al, 2007), to ameliorate tissue damage after myocardial infarction (Abdel-Latif et al, 2007), and to treat graft-versus-host disease (Ringden et al, 2006). Also, attempts are being undertaken to employ MSC as a vehicle for gene therapy, e.g.…”

Section: Introductionmentioning

confidence: 99%

Controversial issue: Is it safe to employ mesenchymal stem cells in cell-based therapies?

Lepperdinger

Brunauer

Jamnig

et al. 2008

Experimental Gerontology

117

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Mesenchymal stem cells for treatment of severe acute graft-versus-host disease

Cited by 104 publications

References 0 publications

IFN‐γ activation of mesenchymal stem cells for treatment and prevention of graft versus host disease

IFN‐γ activation of mesenchymal stem cells for treatment and prevention of graft versus host disease

Derivation and immunological characterization of mesenchymal stromal cells from human embryonic stem cells

Controversial issue: Is it safe to employ mesenchymal stem cells in cell-based therapies?

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