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      Effect of rapamycin on immunity induced by vector-mediated dystrophin expression in mdx skeletal muscle

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene. Therapeutic gene replacement of a dystrophin cDNA into dystrophic muscle can provide functional dystrophin protein to the tissue. However, vector-mediated gene transfer is limited by anti-vector and anti-transgene host immunity that causes rejection of the therapeutic protein. We hypothesized that rapamycin (RAPA) would diminish immunity due to vector-delivered recombinant dystrophin in the adult mdx mouse model for DMD. To test this hypothesis, we injected limb muscle of mdx mice with RAPA-containing, poly-lactic-co-glycolic acid (PLGA) microparticles prior to dystrophin gene transfer and analyzed treated tissue after 6 weeks. RAPA decreased host immunity against vector-mediated dystrophin protein, as demonstrated by decreased cellular infiltrates and decreased anti-dystrophin antibody production. The interpretation of the effect of RAPA on recombinant dystrophin expression was complex because of an effect of PLGA microparticles.

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          The mTOR pathway in the control of protein synthesis.

          Xuemin Wang, Christopher G. Proud (2006)
          Signaling through mammalian target of rapamycin (mTOR) is activated by amino acids, insulin, and growth factors, and impaired by nutrient or energy deficiency. mTOR plays key roles in cell physiology. mTOR regulates numerous components involved in protein synthesis, including initiation and elongation factors, and the biogenesis of ribosomes themselves.
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            Rapamycin inhibits IL-4--induced dendritic cell maturation in vitro and dendritic cell mobilization and function in vivo.

            W Murray Thomson, T Taner, A F Zahorchak … (2003)
            Rapamycin (RAPA) is a potent immunosuppressive macrolide hitherto believed to mediate its action primarily via suppression of lymphocyte responses to interleukin 2 (IL-2) and other growth factors. We show here that this view is incomplete and provide evidence that RAPA suppresses the functional activation of dendritic cells (DCs) both in vitro and in vivo. In vitro, RAPA inhibits IL-4-dependent maturation and T-cell stimulatory activity of murine bone marrow-derived DCs. These effects are associated with posttranscriptional down-regulation of both subunits of the IL-4 receptor complex (CD124, CD132) and are mediated via binding of RAPA to its intracellular receptor FK506-binding protein 12 (FKBP12). In vivo, RAPA impairs steady-state DC generation and fms-like tyrosine 3 kinase ligand (Flt3L)-induced DC mobilization. In addition, in vivo administration of RAPA impairs DC costimulatory molecule up-regulation, production of proinflammatory cytokines, and T-cell allostimulatory capacity. These novel findings have implications for RAPA-based therapy of chronic DC-triggered autoimmune diseases, transplant rejection, and hematologic malignancies with activating Flt3 mutations.
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              Selective survival of naturally occurring human CD4+CD25+Foxp3+ regulatory T cells cultured with rapamycin.

              Christoph Bergmann, Alexander Knuth, Alfred Zippelius … (2007)
              Naturally occurring CD4(+)CD25(+) regulatory T (nTreg) cells are essential for maintaining T cell tolerance to self Ags. We show that discrimination of human Treg from effector CD4(+)CD25(+) non-nTreg cells and their selective survival and proliferation can now be achieved using rapamycin (sirolimus). Human purified CD4(+)CD25(high) T cell subsets stimulated via TCR and CD28 or by IL-2 survived and expanded up to 40-fold in the presence of 1 nM rapamycin, while CD4(+)CD25(low) or CD4(+)CD25(-) T cells did not. The expanding pure populations of CD4(+)CD25(high) T cells were resistant to rapamycin-accelerated apoptosis. In contrast, proliferation of CD4(+)CD25(-) T cells was blocked by rapamycin, which induced their apoptosis. The rapamycin-expanded CD4(+)CD25(high) T cell populations retained a broad TCR repertoire and, like CD4(+) CD25(+) T cells freshly obtained from the peripheral circulation, constitutively expressed CD25, Foxp3, CD62L, glucocorticoid-induced TNFR family related protein, CTLA-4, and CCR-7. The rapamycin-expanded T cells suppressed proliferation and effector functions of allogeneic or autologous CD4(+) and CD8(+) T cells in vitro. They equally suppressed Ag-specific and nonspecific responses. Our studies have defined ex vivo conditions for robust expansion of pure populations of human nTreg cells with potent suppressive activity. It is expected that the availability of this otherwise rare T cell subset for further studies will help define the molecular basis of Treg-mediated suppression in humans.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Sci Rep
                Journal ID (iso-abbrev): Sci Rep
                Title: Scientific Reports
                Publisher: Nature Publishing Group
                ISSN (Electronic): 2045-2322
                Publication date (Electronic): 08 May 2012
                Publication date Collection: 2012
                Volume: 2
                Electronic Location Identifier: 399
                Affiliations
                [1 ]simpleNeurology Service, Department of Veterans Affairs Medical Center , Pittsburgh, PA 15240
                [2 ]simpleDepartment of Neurology, University of Pittsburgh , Pittsburgh, PA 15213
                [3 ]simpleDepartment of Bioengineering, University of Pittsburgh , Pittsburgh, PA 15213
                [4 ]simpleDepartment of Immunology, University of Pittsburgh , Pittsburgh, PA 15213
                [5 ]simpleDepartment of Chemical Engineering, University of Pittsburgh , Pittsburgh, PA 15213
                [6 ]simpleMcGowan Institute for Regenerative Medicine, University of Pittsburgh , Pittsburgh, PA 15219
                [7 ]simpleDepartment of Biochemistry and Molecular Biology, School of Medicine, University of Maryland , Baltimore, MD 21201
                [8 ]simpleDepartment of Anesthesiology, Children's Hospital Boston and David H. Koch Institute of Integrative Cancer Research , MIT, Cambridge, MA 02139
                Author notes
                Article
                Publisher Item ID: srep00399
                DOI: 10.1038/srep00399
                PMC ID: 3347316
                PubMed ID: 22570764
                SO-VID: 54dd1030-8700-4ded-99bf-3abaeb212ed6
                Copyright © Copyright © 2012, Macmillan Publishers Limited. All rights reserved
                License:

                This work is licensed under a Creative Commons Attribution-NonCommercial-ShareALike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/

                History
                Date received : 22 December 2011
                Date accepted : 23 April 2012
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                Subject: Article

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