Measuring the Immunogenicity of Allogeneic Adult Mesenchymal Stem Cells Alix K
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Berglund et al. Stem Cell Research & Therapy (2017) 8:288 DOI 10.1186/s13287-017-0742-8 REVIEW Open Access Immunoprivileged no more: measuring the immunogenicity of allogeneic adult mesenchymal stem cells Alix K. Berglund1*, Lisa A. Fortier2, Douglas F. Antczak3 and Lauren V. Schnabel1* Abstract Background: Autologous and allogeneic adult mesenchymal stem/stromal cells (MSCs) are increasingly being investigated for treating a wide range of clinical diseases. Allogeneic MSCs are especially attractive due to their potential to provide immediate care at the time of tissue injury or disease diagnosis. The prevailing dogma has been that allogeneic MSCs are immune privileged, but there have been very few studies that control for matched or mismatched major histocompatibility complex (MHC) molecule expression and that examine immunogenicity in vivo. Studies that control for MHC expression have reported both cell-mediated and humoral immune responses to MHC-mismatched MSCs. The clinical implications of immune responses to MHC-mismatched MSCs are still unknown. Pre-clinical and clinical studies that document the MHC haplotype of donors and recipients and measure immune responses following MSC treatment are necessary to answer this critical question. Conclusions: This review details what is currently known about the immunogenicity of allogeneic MSCs and suggests contemporary assays that could be utilized in future studies to appropriately identify and measure immune responses to MHC-mismatched MSCs. Keywords: Mesenchymal stem cell, Allogeneic, Immunogenicity, Major histocompatibility complex, Mixed leukocyte reaction, Cytotoxicity, ELISPOT, Microcytotoxicity Background in vivo [9], questioning the relevance of differentiation Mesenchymal stem cells (MSCs) are currently defined as to the therapeutic properties of MSCs when injected in a plastic-adherent cells with a fibroblast-like morphology naive state. Tri-lineage differentiation assays may still be that are capable of differentiating into bone, cartilage, important in some cases for confirming that the cells and fat in vitro and that express a defined set of surface used in studies are MSCs, since MSCs and fibroblasts markers, which vary slightly by species [1, 2]. The origin have similar morphology and phenotype [10]. of MSCs in vivo is controversial, but there is evidence to Secretion of paracrine factors is now recognized as the support that MSCs are a type of pericyte or adventitial primary mechanism by which MSCs promote a regen- cell [3, 4]. The multipotent properties of MSCs led to erative environment conducive to healing with healthy initial conclusions that these cells could be used clinic- tissue [11], although cell-to-cell contact has also been ally to repair or regenerate injured tissues [5], and ani- shown to be important under some conditions [12, 13]. mal studies supported that MSCs provided a therapeutic MSCs home to sites of inflammation where they secrete benefit [6]. However, MSCs have poor engraftment rates a variety of soluble factors including growth factors, [7, 8] and there is little evidence to suggest that the pri- cytokines, and chemokines [14]. In-vivo studies have mary function of MSCs is to differentiate into new tissue demonstrated that MSC therapy promotes angiogenesis and growth and differentiation of local progenitor cells, * Correspondence: [email protected]; [email protected] prevents fibrosis and apoptosis, attracts immune cells to 1Department of Clinical Sciences, College of Veterinary Medicine and the the site of injury, and modulates immune responses Comparative Medicine Institute, North Carolina State University, Raleigh, NC [14–17]. As engraftment appears to be unnecessary for 27607, USA Full list of author information is available at the end of the article the therapeutic effect, exogenous MSCs likely need to © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Berglund et al. Stem Cell Research & Therapy (2017) 8:288 Page 2 of 7 persist through the initial inflammatory phase and into are MHC-matched or MHC-mismatched, nor do they the repair and remodeling phase of tissue healing to investigate if the MSCs induce immune responses and are have a full therapeutic effect. Adult MSCs, which are rejected. Furthermore, few studies have compared allogeneic obtained from the bone marrow, peripheral blood, or versus autologous MSC therapy using cells of comparable adipose tissue of patients, are currently being investi- quality to determine if there is a difference in efficacy for gated in over 450 clinical trials to treat numerous dis- tissue healing or disease outcome and if those differences eases including musculoskeletal diseases, degenerative correlate or not with immune rejection of allogeneic MSCs. and traumatic neurological diseases, and immune- In order to fully understand the potential of allogeneic MSC mediated diseases [18]. MSC therapy has been effective therapy, further investigation into the immune responses at treating several animal models of disease [19, 20] and towards allogeneic cells and if immune responses affect the shown success in human clinical trials [18]. The therapeutic outcome of MSC therapy are warranted. therapeutic benefits of MSC therapy demonstrated in The purposes of this review are to outline what is preclinical trials has not translated to success in every currently understood about immune responses to adult human clinical trial, however, and the use of allogeneic allogeneic MSCs and to describe contemporary assays versus autologous MSC therapy is one factor that may that could be utilized in future preclinical studies and contribute to the differences in efficacy seen in some clinical trials to appropriately identify and measure im- clinical trials [21, 22]. mune responses to allogeneic MSCs. By gaining a better In-vitro expansion of MSCs prior to clinical use can take understanding of how and under what circumstances a several weeks to obtain enough cells for administration, recipient immune system responds to allogeneic MSCs, resulting in loss of stemness; the age and disease state of researchers can develop strategies to improve allogeneic the patient can also negatively affect the quality of the cells MSC efficacy and ensure safety. [23, 24]. Adult allogeneic MSC therapy is particularly at- tractive as it allows for immediate treatment with quality In vivo immunogenicity of allogeneic MSCs cells at the time of injury or diagnosis. In early studies, The few published studies that controlled for MHC researchers discovered that allogeneic MSCs were capable haplotype of donors and recipients and assessed immune of inhibiting the proliferation of major histocompatibility responses following injection of MSCs support that adult complex (MHC)-mismatched lymphocytes in mixed MHC-mismatched MSCs are not immune privileged. In leukocyte reactions (MLR) in vitro [25]. MSCs produce a multiple animal models, bone marrow-derived MHC- variety of immunomodulatory cytokines including trans- mismatched MSCs induced both cell-mediated and forming growth factor-β1, indoleamine 2,3-dioxygenase, humoral immune responses in vivo and were subse- inducible nitric oxide synthase, and prostaglandin E2, quently rejected (Table 1) [29–35]. These studies pro- which contribute to the ability of MSCs to modulate im- vided valuable information about how the immune mune responses [14]. This discovery initially indicated system responds to MHC-mismatched MSCs, although that MSCs were “immunoprivileged” and were subse- the clinical implications of MSC rejection by the recipi- quently promoted as safe to use in allogeneic settings ent immune system are still not entirely clear. without concern for immune rejection [25]. Cell-mediated responses to MSCs are induced when T Although allogeneic MSC therapy is generally regarded as cells become activated following recognition of foreign safe [26], there have been several reports of adverse clinical donor MHC molecules expressed on the surface of the events including increased synovial cellularity and total MSCs. Significant increases in circulating T cells and nucleated cell counts following intra-articular injection of natural killer cells were detected in rhesus macaques as allogeneic MSCs in equine models [27, 28]. Most studies do early as 10 days after intracranial injection with MHC- not characterize if allogeneic donor MSCs and recipients mismatched MSCs, but not those injected with Table 1 In-vivo studies with MHC controls and immune response analysis Author Species Cell-mediated Humoral In vivo rejection Methods used Eliopoulos and Stagg, 2005 [29] Mouse + + In-vivo cytotoxicity Nauta et al., 2006 [30] Mouse + + In-vivo cytotoxicity Badillo et al., 2007 [31] Mouse + + Ex-vivo MLR, allograft rejection Poncelet et al., 2007 [32] Pig + + Ex-vivo MLR, CDC Zangi et al., 2009 [33] Mouse + + + Allograft rejection, in-vivo imaging Isakova et al., 2014 [34] Rhesus Macaques + In-vitro cytotoxicity Pezzanite et al., 2015 [35] Horse + CDC CDC complement-dependent