Abstract
Treatment with glatiramer acetate (GA, copolymer-1, Copaxone), a drug approved for multiple sclerosis (MS), in a mouse model promoted development of anti-inflammatory type II monocytes, characterized by increased secretion of interleukin (IL)-10 and transforming growth factor (TGF)-β, and decreased production of IL-12 and tumor necrosis factor (TNF). This anti-inflammatory cytokine shift was associated with reduced STAT-1 signaling. Type II monocytes directed differentiation of TH2 cells and CD4+CD25+FoxP3+ regulatory T cells (Treg) independent of antigen specificity. Type II monocyte–induced regulatory T cells specific for a foreign antigen ameliorated experimental autoimmune encephalomyelitis (EAE), indicating that neither GA specificity nor recognition of self-antigen was required for their therapeutic effect. Adoptive transfer of type II monocytes reversed EAE, suppressed TH17 cell development and promoted both TH2 differentiation and expansion of Treg cells in recipient mice. This demonstration of adoptive immunotherapy by type II monocytes identifies a central role for these cells in T cell immune modulation of autoimmunity.
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References
Johnson, K.P. et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind, placebo-controlled trial. Neurology 45, 1268–1276 (1995).
Neuhaus, O., Farina, C., Wekerle, H. & Hohlfeld, R. Mechanisms of action of glatiramer acetate in multiple sclerosis. Neurology 56, 702–708 (2001).
Farina, C., Weber, M.S., Meinl, E., Wekerle, H. & Hohlfeld, R. Glatiramer acetate in multiple sclerosis: update on potential mechanisms of action. Lancet Neurol. 4, 567–575 (2005).
Fridkis-Hareli, M. et al. Direct binding of myelin basic protein and synthetic copolymer 1 to class II major histocompatibility complex molecules on living antigen-presenting cells–specificity and promiscuity. Proc. Natl. Acad. Sci. USA 91, 4872–4876 (1994).
Teitelbaum, D., Fridkis-Hareli, M., Arnon, R. & Sela, M. Copolymer 1 inhibits chronic relapsing experimental allergic encephalomyelitis induced by proteolipid protein (PLP) peptides in mice and interferes with PLP-specific T cell responses. J. Neuroimmunol. 64, 209–217 (1996).
Neuhaus, O. et al. Multiple sclerosis: comparison of copolymer-1- reactive T cell lines from treated and untreated subjects reveals cytokine shift from T helper 1 to T helper 2 cells. Proc. Natl. Acad. Sci. USA 97, 7452–7457 (2000).
Dhib-Jalbut, S. Mechanisms of action of interferons and glatiramer acetate in multiple sclerosis. Neurology 58, S3–S9 (2002).
Duda, P.W., Schmied, M.C., Cook, S.L., Krieger, J.I. & Hafler, D.A. Glatiramer acetate (Copaxone) induces degenerate, Th2-polarized immune responses in patients with multiple sclerosis. J. Clin. Invest. 105, 967–976 (2000).
Aharoni, R., Teitelbaum, D., Sela, M. & Arnon, R. Copolymer 1 induces T cells of the T helper type 2 that crossreact with myelin basic protein and suppress experimental autoimmune encephalomyelitis. Proc. Natl. Acad. Sci. USA 94, 10821–10826 (1997).
Aharoni, R. et al. Specific Th2 cells accumulate in the central nervous system of mice protected against experimental autoimmune encephalomyelitis by copolymer 1. Proc. Natl. Acad. Sci. USA 97, 11472–11477 (2000).
Chen, M. et al. Glatiramer acetate induces a Th2-biased response and crossreactivity with myelin basic protein in patients with MS. Mult. Scler. 7, 209–219 (2001).
Ziemssen, T., Kumpfel, T., Klinkert, W.E., Neuhaus, O. & Hohlfeld, R. Glatiramer acetate-specific T-helper 1- and 2-type cell lines produce BDNF: implications for multiple sclerosis therapy. Brain-derived neurotrophic factor. Brain 125, 2381–2391 (2002).
Weber, M.S. et al. Multiple sclerosis: glatiramer acetate inhibits monocyte reactivity in vitro and in vivo. Brain 127, 1370–1378 (2004).
Kim, H.J. et al. Type 2 monocyte and microglia differentiation mediated by glatiramer acetate therapy in patients with multiple sclerosis. J. Immunol. 172, 7144–7153 (2004).
Vieira, P.L., Heystek, H.C., Wormmeester, J., Wierenga, E.A. & Kapsenberg, M.L. Glatiramer acetate (copolymer-1, copaxone) promotes Th2 cell development and increased IL-10 production through modulation of dendritic cells. J. Immunol. 170, 4483–4488 (2003).
Stasiolek, M. et al. Impaired maturation and altered regulatory function of plasmacytoid dendritic cells in multiple sclerosis. Brain 129, 1293–1305 (2006).
Stuve, O. et al. Immunomodulatory synergy by combination of atorvastatin and glatiramer acetate in treatment of CNS autoimmunity. J. Clin. Invest. 116, 1037–1044 (2006).
Takahashi, K., Prinz, M., Stagi, M., Chechneva, O. & Neumann, H. TREM2-transduced myeloid precursors mediate nervous tissue debris clearance and facilitate recovery in an animal model of multiple sclerosis. PLoS Med. 4, e124 (2007).
Zamora, A., Matejuk, A., Silverman, M., Vandenbark, A.A. & Offner, H. Inhibitory effects of incomplete Freund's adjuvant on experimental autoimmune encephalomyelitis. Autoimmunity 35, 21–28 (2002).
Kuchroo, V.K. et al. B7–1 and B7–2 costimulatory molecules activate differentially the Th1/Th2 developmental pathways: application to autoimmune disease therapy. Cell 80, 707–718 (1995).
Ranger, A.M., Das, M.P., Kuchroo, V.K. & Glimcher, L.H. B7–2 (CD86) is essential for the development of IL-4-producing T cells. Int. Immunol. 8, 1549–1560 (1996).
Salama, A.D. et al. Critical role of the programmed death-1 (PD-1) pathway in regulation of experimental autoimmune encephalomyelitis. J. Exp. Med. 198, 71–78 (2003).
Wesemann, D.R. & Benveniste, E.N. STAT-1 alpha and IFN-gamma as modulators of TNF-alpha signaling in macrophages: regulation and functional implications of the TNF receptor 1:STAT-1 alpha complex. J. Immunol. 171, 5313–5319 (2003).
Flesch, I.E. et al. Early interleukin 12 production by macrophages in response to mycobacterial infection depends on interferon gamma and tumor necrosis factor alpha. J. Exp. Med. 181, 1615–1621 (1995).
VanDeusen, J.B. et al. STAT-1-mediated repression of monocyte interleukin-10 gene expression in vivo. Eur. J. Immunol. 36, 623–630 (2006).
Chitnis, T. et al. Effect of targeted disruption of STAT4 and STAT6 on the induction of experimental autoimmune encephalomyelitis. J. Clin. Invest. 108, 739–747 (2001).
Mombaerts, P. et al. RAG-1-deficient mice have no mature B and T lymphocytes. Cell 68, 869–877 (1992).
Hori, S., Nomura, T. & Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057–1061 (2003).
Brunkow, M.E. et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat. Genet. 27, 68–73 (2001).
Viglietta, V., Baecher-Allan, C., Weiner, H.L. & Hafler, D.A. Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J. Exp. Med. 199, 971–979 (2004).
Kukreja, A. et al. Multiple immuno-regulatory defects in type-1 diabetes. J. Clin. Invest. 109, 131–140 (2002).
Hong, J., Li, N., Zhang, X., Zheng, B. & Zhang, J.Z. Induction of CD4+CD25+ regulatory T cells by copolymer-I through activation of transcription factor Foxp3. Proc. Natl. Acad. Sci. USA 102, 6449–6454 (2005).
Putheti, P., Soderstrom, M., Link, H. & Huang, Y.M. Effect of glatiramer acetate (Copaxone) on CD4+CD25high T regulatory cells and their IL-10 production in multiple sclerosis. J. Neuroimmunol. 144, 125–131 (2003).
Aharoni, R., Teitelbaum, D., Sela, M. & Arnon, R. Bystander suppression of experimental autoimmune encephalomyelitis by T cell lines and clones of the Th2 type induced by copolymer 1. J. Neuroimmunol. 91, 135–146 (1998).
Harrington, L.E. et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat. Immunol. 6, 1123–1132 (2005).
Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006).
Shimoda, M. et al. Conditional ablation of MHC-II suggests an indirect role for MHC-II in regulatory CD4 T cell maintenance. J. Immunol. 176, 6503–6511 (2006).
Steinman, L. & Zamvil, S.S. How to successfully apply animal studies in experimental allergic encephalomyelitis to research on multiple sclerosis. Ann. Neurol. 60, 12–21 (2006).
Nestle, F.O. Dendritic cell vaccination for cancer therapy. Oncogene 19, 6673–6679 (2000).
Frisullo, G. et al. pSTAT1, pSTAT3, and T-bet expression in peripheral blood mononuclear cells from relapsing-remitting multiple sclerosis patients correlates with disease activity. J. Neurosci. Res. 84, 1027–1036 (2006).
Tran, E.H., Hoekstra, K., van Rooijen, N., Dijkstra, C.D. & Owens, T. Immune invasion of the central nervous system parenchyma and experimental allergic encephalomyelitis, but not leukocyte extravasation from blood, are prevented in macrophage-depleted mice. J. Immunol. 161, 3767–3775 (1998).
Jee, Y. et al. Do Th2 cells mediate the effects of glatiramer acetate in experimental autoimmune encephalomyelitis? Int. Immunol. 18, 537–544 (2006).
Lisak, R.P., Zweiman, B., Blanchard, N. & Rorke, L.B. Effect of treatment with Copolymer 1 (Cop-1) on the in vivo and in vitro manifestations of experimental allergic encephalomyelitis (EAE). J. Neurol. Sci. 62, 281–293 (1983).
Thornton, A.M. & Shevach, E.M. Suppressor effector function of CD4+CD25+ immunoregulatory T cells is antigen nonspecific. J. Immunol. 164, 183–190 (2000).
Zamvil, S. et al. T cell clones specific for myelin basic protein induce relapsing EAE and demyelination. Nature 317, 355–358 (1985).
Zhang, M. et al. Copolymer 1 inhibits experimental autoimmune uveoretinitis. J. Neuroimmunol. 103, 189–194 (2000).
Gur, C. et al. Amelioration of experimental colitis by Copaxone is associated with class-II-restricted CD4 immune blocking. Clin. Immunol. 118, 307–316 (2006).
Arnon, R. & Aharoni, R. Mechanism of action of glatiramer acetate in multiple sclerosis and its potential for the development of new applications. Proc. Natl. Acad. Sci. USA 101(suppl. 2), 14593–14598 (2004).
Hardardottir, F., Baron, J.L. & Janeway, C.A., Jr. T cells with two functional antigen-specific receptors. Proc. Natl. Acad. Sci. USA 92, 354–358 (1995).
Bettelli, E. et al. Myelin oligodendrocyte glycoprotein-specific T cell receptor transgenic mice develop spontaneous autoimmune optic neuritis. J. Exp. Med. 197, 1073–1081 (2003).
Acknowledgements
We thank A.J. Slavin, P.H. Lalive, R. Hohlfeld, J.A. Bluestone, O. Neuhaus, J.R. Oksenberg and S.L. Hauser for discussions. M.S.W. is a fellow of the Deutsche Forschungsgemeinschaft (DFG) and of the National Multiple Sclerosis Society (NMSS). T.P. and S.E.D. are fellows of the NMSS. S.Y. is supported by the NMSS Career Transitional award. Support for this work was provided to S.S.Z. by the US National Institutes of Health (NIH) (RO1 NS046721 and RO1 AI059709), the NMSS (RG 3206B and RG 3622A), the Maisin Foundation, Teva Neuroscience, Inc. and the Dana Foundation; to L.S. by the NIH (RO1 AI059709) and NMSS (CA1030A9 and RG 3622-A); and to R.A.S. by the NIH (NS06414). O.S. is supported by a Start-up grant from the Dallas VA Research Corporation, and a New Investigator Award grant from VISN 17, US Veterans Affairs.
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M.S.W. conducted most of the experiments, prepared the figures and participated in writing the manuscript. T.P., S.Y. and S.E.D. performed the western blot analysis for STAT1 phosphorylation. C.D.R., L.L. and J.C.P. participated in the characterization of type II monocytes in vitro and in vivo. O.S. and L.S. participated in the experimental design and in editing the manuscript. R.A.S. conducted the histological analyses. S.S.Z. initiated and supervised the project and participated in writing the manuscript.
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Weber, M., Prod'homme, T., Youssef, S. et al. Type II monocytes modulate T cell–mediated central nervous system autoimmune disease. Nat Med 13, 935–943 (2007). https://doi.org/10.1038/nm1620
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DOI: https://doi.org/10.1038/nm1620
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