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      Immunoprivileged no more: measuring the immunogenicity of allogeneic adult mesenchymal stem cells

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          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.

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          Most cited references33

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          Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms.

          Severe acute renal failure (ARF) remains a common, largely treatment-resistant clinical problem with disturbingly high mortality rates. Therefore, we tested whether administration of multipotent mesenchymal stem cells (MSC) to anesthetized rats with ischemia-reperfusion-induced ARF (40-min bilateral renal pedicle clamping) could improve the outcome through amelioration of inflammatory, vascular, and apoptotic/necrotic manifestations of ischemic kidney injury. Accordingly, intracarotid administration of MSC (approximately 10(6)/animal) either immediately or 24 h after renal ischemia resulted in significantly improved renal function, higher proliferative and lower apoptotic indexes, as well as lower renal injury and unchanged leukocyte infiltration scores. Such renoprotection was not obtained with syngeneic fibroblasts. Using in vivo two-photon laser confocal microscopy, fluorescence-labeled MSC were detected early after injection in glomeruli, and low numbers attached at microvasculature sites. However, within 3 days of administration, none of the administered MSC had differentiated into a tubular or endothelial cell phenotype. At 24 h after injury, expression of proinflammatory cytokines IL-1beta, TNF-alpha, IFN-gamma, and inducible nitric oxide synthase was significantly reduced and that of anti-inflammatory IL-10 and bFGF, TGF-alpha, and Bcl-2 was highly upregulated in treated kidneys. We conclude that the early, highly significant renoprotection obtained with MSC is of considerable therapeutic promise for the cell-based management of clinical ARF. The beneficial effects of MSC are primarily mediated via complex paracrine actions and not by their differentiation into target cells, which, as such, appears to be a more protracted response that may become important in late-stage organ repair.
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            Mesenchymal stem cells are short-lived and do not migrate beyond the lungs after intravenous infusion

            Mesenchymal stem cells (MSC) are under investigation as a therapy for a variety of disorders. Although animal models show long term regenerative and immunomodulatory effects of MSC, the fate of MSC after infusion remains to be elucidated. In the present study the localization and viability of MSC was examined by isolation and re-culture of intravenously infused MSC. C57BL/6 MSC (500,000) constitutively expressing DsRed-fluorescent protein and radioactively labeled with Cr-51 were infused via the tail vein in wild-type C57BL/6 mice. After 5 min, 1, 24, or 72 h, mice were sacrificed and blood, lungs, liver, spleen, kidneys, and bone marrow removed. One hour after MSC infusion the majority of Cr-51 was found in the lungs, whereas after 24 h Cr-51 was mainly found in the liver. Tissue cultures demonstrated that viable donor MSC were present in the lungs up to 24 h after infusion, after which they disappeared. No viable MSC were found in the other organs examined at any time. The induction of ischemia-reperfusion injury in the liver did not trigger the migration of viable MSC to the liver. These results demonstrate that MSC are short-lived after i.v. infusion and that viable MSC do not pass the lungs. Cell debris may be transported to the liver. Long term immunomodulatory and regenerative effects of infused MSC must therefore be mediated via other cell types.
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              Biodistribution, migration and homing of systemically applied mesenchymal stem/stromal cells

              Mesenchymal stem/stromal cells (MSCs) are increasingly used as an intravenously applied cellular therapeutic. They were found to be potent in situations such as tissue repair or severe inflammation. Still, data are lacking with regard to the biodistribution of MSCs, their cellular or molecular target structures, and the mechanisms by which MSCs reach these targets. This review discusses current hypotheses for how MSCs can reach tissue sites. Both preclinical and clinical studies using MSCs applied intravenously or intra-arterially are discussed in the context of our current understanding of how MSCs might work in physiological and pathological situations.
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                Author and article information

                Contributors
                919-513-7213 , akberglu@ncsu.edu
                laf4@cornell.edu
                dfa1@cornell.edu
                919-515-7410 , lvschnab@ncsu.edu
                Journal
                Stem Cell Res Ther
                Stem Cell Res Ther
                Stem Cell Research & Therapy
                BioMed Central (London )
                1757-6512
                22 December 2017
                22 December 2017
                2017
                : 8
                : 288
                Affiliations
                [1 ]ISNI 0000 0001 2173 6074, GRID grid.40803.3f, Department of Clinical Sciences, College of Veterinary Medicine and the Comparative Medicine Institute, , North Carolina State University, ; Raleigh, NC 27607 USA
                [2 ]ISNI 000000041936877X, GRID grid.5386.8, Department of Clinical Sciences, , College of Veterinary Medicine, Cornell University, ; Ithaca, NY 14853 USA
                [3 ]ISNI 000000041936877X, GRID grid.5386.8, Baker Institute for Animal Health, , Cornell University, ; Ithaca, NY 14853 USA
                Article
                742
                10.1186/s13287-017-0742-8
                5741939
                29273086
                3122ef81-1946-4b5e-adeb-770f85912302
                © The Author(s). 2017

                Open AccessThis 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.

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                © The Author(s) 2017

                Molecular medicine
                mesenchymal stem cell,allogeneic,immunogenicity,major histocompatibility complex,mixed leukocyte reaction,cytotoxicity,elispot,microcytotoxicity

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