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      Immunosuppression for in vivo research: state-of-the-art protocols and experimental approaches

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          Abstract

          Almost every experimental treatment strategy using non-autologous cell, tissue or organ transplantation is tested in small and large animal models before clinical translation. Because these strategies require immunosuppression in most cases, immunosuppressive protocols are a key element in transplantation experiments. However, standard immunosuppressive protocols are often applied without detailed knowledge regarding their efficacy within the particular experimental setting and in the chosen model species. Optimization of such protocols is pertinent to the translation of experimental results to human patients and thus warrants further investigation. This review summarizes current knowledge regarding immunosuppressive drug classes as well as their dosages and application regimens with consideration of species-specific drug metabolization and side effects. It also summarizes contemporary knowledge of novel immunomodulatory strategies, such as the use of mesenchymal stem cells or antibodies. Thus, this review is intended to serve as a state-of-the-art compendium for researchers to refine applied experimental immunosuppression and immunomodulation strategies to enhance the predictive value of preclinical transplantation studies.

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          Most cited references284

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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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            The mechanism of action of cyclosporin A and FK506.

            CsA and FK506 are powerful suppressors of the immune system, most notably of T cells. They act at a point in activation that lies between receptor ligation and the transcription of early genes. Here, Stuart Schreiber and Gerald Crabtree review recent findings that indicate CsA and FK506 operate as prodrugs: they bind endogenous intracellular receptors, the immunophilins, and the resulting complex targets the protein phosphatase, calcineurin, to exert the immunosuppressive effect.
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              Mechanisms of action of antithymocyte globulin: T-cell depletion and beyond.

              M Mohty (2007)
              The success of allogeneic stem cell transplantation and solid-organ transplantation owes much to improvements in the immunosuppressive regimens that prevent graft-versus-host disease (GVHD) or suppress allograft rejection. A better understanding of the immune mechanisms underlying induction of immunological tolerance is the key to successful transplantation. Polyclonal antibodies such as antithymocyte globulins (ATG) have been used for decades. The common belief is that ATG efficacy relies on its capacity to deplete T lymphocytes. The aim of this review is to offer an overview of the recent findings that have been demonstrated in ATG's immunomodulatory activity. The polyclonal nature of ATG is reflected in its diverse effects on the immune system: (1) T-cell depletion in blood and peripheral lymphoid tissues through complement-dependent lysis and T-cell activation and apoptosis; (2) modulation of key cell surface molecules that mediate leukocyte/endothelium interactions; (3) induction of apoptosis in B-cell lineages; (4) interference with dendritic cell functional properties; and (5) induction of regulatory T and natural killer T cells. As a consequence, ATG provides multifaceted immunomodulation paving the way for future applications and suggesting that the use of ATG should be included in the immunosuppression therapeutic armamentarium to help reduce the incidence of organ rejection and GVHD.
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                Author and article information

                Journal
                Cell Mol Immunol
                Cell. Mol. Immunol
                Cellular and Molecular Immunology
                Nature Publishing Group
                1672-7681
                2042-0226
                February 2017
                10 October 2016
                1 February 2017
                : 14
                : 2
                : 146-179
                Affiliations
                [1 ]Fraunhofer-Institute for Cell Therapy and Immunology , Leipzig 04103, Germany
                [2 ]Institute of Vegetative Physiology, Charite University Medicine and Center for Cardiovascular Research , Berlin 10115, Germany
                [3 ]University of Newcastle , Callaghan, NSW 2308, Australia
                [4 ]Fraunhofer Research Institution for Marine Biotechnology and Institute for Medical and Marine Biotechnology, University of Lübeck , Lübeck 23562, Germany
                Author notes
                [* ]Medical Cell Technologies, Fraunhofer Research Institution for Marine Biotechnology , Mönkhofer Weg 239a, Lübeck 23562, Germany. E-mail: johannes.boltze@ 123456emb.fraunhofer.de
                [5]

                These authors contributed equally to this work.

                Article
                cmi201639
                10.1038/cmi.2016.39
                5301156
                27721455
                f1f6440d-4d3a-4099-975b-8e0e5a2c084a
                Copyright © 2017 The Author(s)

                This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/

                History
                : 24 November 2015
                : 30 May 2016
                : 30 May 2016
                Categories
                Review

                Immunology
                animal models,immunomodulation,immunosuppression,transplantation,translational research
                Immunology
                animal models, immunomodulation, immunosuppression, transplantation, translational research

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