Clinical scale expanded adult pluripotent stem cells prevent graft-versus-host disease

Kovacsovics-Bankowski, Magdalena; Streeter, Philip R.; Mauch, Kelsey A.; Frey, Mark R.; Raber, Amy; Hof, Wouter van t.; Deans, Robert; Maziarz, Richard T.

doi:10.1016/j.cellimm.2008.10.004

Cited by 55 publications

(53 citation statements)

References 31 publications

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“…To our knowledge, only one recent report has described the immunosuppressive potential of rat-derived MAPCs. 46 Similar to our results, rat MAPCs inhibited alloresponses via a contact-independent mechanism. In contrast to our results, rat MAPC-induced inhibition of T-cell alloproliferation in vitro was dependent upon IDO expression because 1MT reverses the suppressive effects of rat MAPCs.…”

Section: Mapcs Suppress T-cell Alloresponses 699supporting

confidence: 80%

Multipotent adult progenitor cells can suppress graft-versus-host disease via prostaglandin E2 synthesis and only if localized to sites of allopriming

Highfill

Kelly

O’Shaughnessy

et al. 2009

Blood

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IntroductionThe wider application of bone marrow transplantation (BMT) has been limited, in part, by graft-versus-host disease (GVHD) complications. Human and mouse mesenchymal stem cells (MSCs) have been shown to suppress allogeneic-induced and nonspecific mitogen-induced T-cell proliferation in vitro (reviewed in detail 1,2 ). Implicated suppressive mechanisms have included interleukin (IL)-10, 3 transforming growth factor (TGF)-␤, hepatocyte growth factor, 4 indoleamine 2,3 dioxygenase (IDO), 5 nitric oxide, 6 prostaglandin (PG) E 2 , 7 increased T-regulatory cells (Tregs), 8 and activation of the PD-1-negative costimulatory pathway. 9 In vivo, there have been conflicting data regarding the potential of MSCs to suppress GVHD. [10][11][12] Multipotent adult progenitor cells (MAPCs) are nonhematopoietic stem cells that can be copurified with MSCs from BM cells. MAPCs express the pluripotent state-specific transcription factors Oct-3/4 and Rex-1, and can differentiate into cell types representative of all 3 germ layers 13,14 ; thus, MAPCs are generally believed to be a more primitive cell type than MSCs. MSCs kept for prolonged periods in culture tend to lose their differentiation capabilities and undergo senescence at approximately 20 to 40 population doublings. 15,16 In contrast to MSCs, MAPCs have an average telomere length that remained constant for up to 100 population doublings in vitro. 13 Based upon their differential potential and reduced senescence, MAPCs have been considered as a potentially desirable nonhematopoietic stem cell source for use in allogeneic BMT. In fact, a multicenter phase 1 open label clinical trial of MultiStem, based upon MAPC technology, was initiated in 2008.In this study, we sought to determine whether MAPCs might be useful for GVHD prevention. We demonstrate that murine MAPCs are potently immune suppressive in vitro and can reduce GVHD lethality in vivo when present in the spleen, a site of initial allopriming, early post-BMT. Furthermore, we identify the mechanism of action MAPCs use to elicit T-cell inhibition and reduce GVHD-induced tissue injury in vivo. Methods MiceBALB/c (H2 d ), C57BL/6 (H2 b ; termed B6), and B10.BR (H2 k ) mice were purchased from The Jackson Laboratory or the National Institutes of Health (NIH). All mice were housed in a specific pathogen-free facility in microisolator cages and used at 8 to 12 weeks of age in protocols approved by the Institutional Animal Care and Use Committee of the University of Minnesota. MAPC isolation and cultureMAPCs were isolated from B6 and BALB/c BM, as described. 13 Briefly, BM was plated in Dulbecco modified Eagle medium/MCDB containing 10 ng/mL epidermal growth factor (Sigma-Aldrich), platelet-derived growth factor-BB (R&D Systems), leukemia inhibitory factor (Chemicon International), 2% fetal calf serum (HyClone), 1ϫ selenium-insulin-transferrinethanolamine, 0.2 mg/mL linoleic acid-bovine serum albumin (BSA), 0.8 mg/mL BSA, 1ϫ chemically defined lipid concentrate, and 1ϫ ␣-mercaptoethanol (all from Sigma-Aldrich). Cells...

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Section: Mapcs Suppress T-cell Alloresponses 699supporting

confidence: 80%

Multipotent adult progenitor cells can suppress graft-versus-host disease via prostaglandin E2 synthesis and only if localized to sites of allopriming

Highfill

Kelly

O’Shaughnessy

et al. 2009

Blood

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“…Human MAPCs can be distinguished from human MSCs on the basis of cell surface phenotype, cell size, transcriptional profile, cytokine production, differentiation potential and replicative capacity (6, 10, 34, 35). Previous work showed that murine MAPCs exert therapeutic immunomodulatory effects in the context of graft-versus-host disease prophylaxis, in MLR systems in vitro, and that human MAPCs prevented inflammation in a murine model of stroke, supporting a role for these cells in treating human immune-mediated diseases (36)(37)(38).…”

Section: Discussionmentioning

confidence: 99%

Clinical-Grade Multipotent Adult Progenitor Cells Durably Control Pathogenic T Cell Responses in Human Models of Transplantation and Autoimmunity

Reading

Yang

Sabbah

et al. 2013

The Journal of Immunology

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A major goal of immunotherapy remains the control of pathogenic T cell responses that drive autoimmunity and allograft rejection. Adherent progenitor cells, including mesenchymal stromal cells (MSCs) and multipotent adult progenitor cells (MAPCs), represent attractive immunomodulatory cell therapy candidates currently active in clinical trials. MAPCs can be distinguished from MSCs on the basis of cellular phenotype, size, transcriptional profile, and expansion capacity. However, despite their ongoing evaluation in autoimmune and allogeneic solid organ transplantation settings, data supporting the immune regulatory potential of clinical-grade MAPCs are limited. In this study, we used allogeneic islet transplantation as a model indication to assess the ability of clinical-grade MAPCs to control T cell responses that drive immunopathology in human autoimmune disease and allograft rejection. MAPCs suppressed T cell proliferation and Th1 and Th17 cytokine production while increasing secretion of IL-10 and were able to suppress effector functions of bona fide autoreactive T cells from individuals with type 1 diabetes mellitus, including killing of human islets. Furthermore, MAPCs favored the proliferation of regulatory T cells during homeostatic expansion driven by γ-chain cytokines and exerted a durable, yet reversible, control of T cell function. MAPC suppression required licensing and proceeded via IDO-mediated tryptophan catabolism. Therefore, the common immune modulatory characteristics of clinical-grade MAPCs shown in this study suggest that they can be regarded as an alternative source of adult progenitor cells with similar clinical usefulness to MSCs. Taken collectively, these findings may guide the successful deployment of both MSCs and MAPCs for the amelioration of human autoimmunity and allograft rejection.

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“…No cellbased therapeutics are currently on the market for treating stroke, which had an estimated cost of over $68.9 billion dollars to patients in both direct and indirect costs in the United States alone in 2009 (LloydJones et al 2009). Pre-clinical animal studies point to benefit derived from transplanted stem cells following ischemic injury in the CNS (Chen et al 2001c;Chen et al 2003b;Li and Chopp 2009;Ohtaki et al 2008;Shyu et al 2006;Yasuhara et al 2008;Yasuhara et al 2006b;Zhao et al 2002), in the heart (reviewed in (Charwat et al 2008;Ting et al 2008)), the peripheral vasculature (Aranguren et al 2008) and other inflammatory injury models (Aggarwal and Pittenger 2005;Kovacsovics-Bankowski et al 2008;Kovacsovics-Bankowski et al 2009). …”

Section: Introductionmentioning

confidence: 99%

Development of an allogeneic adherent stem cell therapy for treatment of ischemic stroke

Mays¹,

Borlongan²,

Yasuhara³

et al. 2010

J Exp Stroke Transl Med

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Clinical scale expanded adult pluripotent stem cells prevent graft-versus-host disease

Cited by 55 publications

References 31 publications

Multipotent adult progenitor cells can suppress graft-versus-host disease via prostaglandin E2 synthesis and only if localized to sites of allopriming

Multipotent adult progenitor cells can suppress graft-versus-host disease via prostaglandin E2 synthesis and only if localized to sites of allopriming

Clinical-Grade Multipotent Adult Progenitor Cells Durably Control Pathogenic T Cell Responses in Human Models of Transplantation and Autoimmunity

Development of an allogeneic adherent stem cell therapy for treatment of ischemic stroke

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