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      Dichotomic Potency of IFNγ Licensed Allogeneic Mesenchymal Stromal Cells in Animal Models of Acute Radiation Syndrome and Graft Versus Host Disease

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          Abstract

          Mesenchymal stromal cells (MSCs) are being tested as a cell therapy in clinical trials for dozens of inflammatory disorders, with varying levels of efficacy reported. Suitable and robust preclinical animal models for testing the safety and efficacy of different types of MSC products before use in clinical trials are rare. We here introduce two highly robust animal models of immune pathology: 1) acute radiation syndrome (ARS) and 2) graft versus host disease (GvHD), in conjunction with studying the immunomodulatory effect of well-characterized Interferon gamma (IFNγ) primed bone marrow derived MSCs. The animal model of ARS is based on clinical grade dosimetry precision and bioluminescence imaging. We found that allogeneic MSCs exhibit lower persistence in naïve compared to irradiated animals, and that intraperitoneal infusion of IFNγ prelicensed allogeneic MSCs protected animals from radiation induced lethality by day 30. In direct comparison, we also investigated the effect of IFNγ prelicensed allogeneic MSCs in modulating acute GvHD in an animal model of MHC major mismatched bone marrow transplantation. Infusion of IFNγ prelicensed allogeneic MSCs failed to mitigate acute GvHD. Altogether our results demonstrate that infused IFNγ prelicensed allogeneic MSCs protect against lethality from ARS, but not GvHD, thus providing important insights on the dichotomy of IFNγ prelicensed allogenic MSCs in well characterized and robust animal models of acute tissue injury.

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          Most cited references57

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          Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells.

          Adult bone-marrow-derived mesenchymal stem cells are immunosuppressive and prolong the rejection of mismatched skin grafts in animals. We transplanted haploidentical mesenchymal stem cells in a patient with severe treatment-resistant grade IV acute graft-versus-host disease of the gut and liver. Clinical response was striking. The patient is now well after 1 year. We postulate that mesenchymal stem cells have a potent immunosuppressive effect in vivo.
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            Mesenchymal stem cells: immune evasive, not immune privileged.

            The diverse immunomodulatory properties of mesenchymal stem/stromal cells (MSCs) may be exploited for treatment of a multitude of inflammatory conditions. MSCs have long been reported to be hypoimmunogenic or 'immune privileged'; this property is thought to enable MSC transplantation across major histocompatibility barriers and the creation of off-the-shelf therapies consisting of MSCs grown in culture. However, recent studies describing generation of antibodies against and immune rejection of allogeneic donor MSCs suggest that MSCs may not actually be immune privileged. Nevertheless, whether rejection of donor MSCs influences the efficacy of allogeneic MSC therapies is not known, and no definitive clinical advantage of autologous MSCs over allogeneic MSCs has been demonstrated to date. Although MSCs may exert therapeutic function through a brief 'hit and run' mechanism, protecting MSCs from immune detection and prolonging their persistence in vivo may improve clinical outcomes and prevent patient sensitization toward donor antigens.
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              Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn's disease: a phase 3 randomised, double-blind controlled trial

              Complex perianal fistulas in Crohn's disease are challenging to treat. Allogeneic, expanded, adipose-derived stem cells (Cx601) are a promising new therapeutic approach. We aimed to assess the safety and efficacy of Cx601 for treatment-refractory complex perianal fistulas in patients with Crohn's disease.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                26 July 2021
                2021
                : 12
                : 708950
                Affiliations
                [1] 1Department of Biomedical Sciences, Mercer University School of Medicine , Savannah, GA, United States
                [2] 2Department of Pediatrics, University of Wisconsin School of Medicine and Public Health , Madison, WI, United States
                [3] 3Department of Medical Physics, University of Wisconsin School of Medicine and Public Health , Madison, WI, United States
                [4] 4Department of Human Oncology, University of Wisconsin School of Medicine and Public Health , Madison, WI, United States
                [5] 5University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health , Madison, WI, United States
                [6] 6Department of Medicine, University of Wisconsin School of Medicine and Public Health , Madison, WI, United States
                Author notes

                Edited by: Guido Moll, Charité–Universitätsmedizin Berlin, Germany

                Reviewed by: Mehdi Najar, Université libre de Bruxelles, Belgium; Selim Kuci, University Hospital Frankfurt, Germany

                *Correspondence: Raghavan Chinnadurai, chinnadurai_r@ 123456mercer.edu

                This article was submitted to Alloimmunity and Transplantation, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2021.708950
                8352793
                34386012
                f016c5c9-a49d-4306-8ea6-cee87b944a35
                Copyright © 2021 Chinnadurai, Bates, Kunugi, Nickel, DeWerd, Capitini, Galipeau and Kimple

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 12 May 2021
                : 01 July 2021
                Page count
                Figures: 5, Tables: 0, Equations: 0, References: 57, Pages: 10, Words: 4831
                Categories
                Immunology
                Original Research

                Immunology
                mesenchymal stromal/stem cells,interferon-γ,cell therapy,acute radiation injury,bone marrow transplantation,animal model

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