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Type II monocytes modulate T cell–mediated central nervous system autoimmune disease

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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Figure 1: GA prevents and reverses established EAE, promoting a TH2 bias and development of CD4+CD25+FoxP3+ regulatory T cells.
Figure 2: GA treatment induces type II monocytes.
Figure 3: Type II monocytes direct naive T cells to differentiate into TH2 cells and CD4+CD25+FoxP3+ regulatory T cells independent of antigen specificity.
Figure 4: GA treatment induces GA-reactive T cells that do not cross-react with myelin antigens.
Figure 5: GA-induced type II monocytes reverse clinical and histologic EAE in recipient mice.
Figure 6: GA-induced type II monocytes direct T cell immune regulation in vivo.

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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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Correspondence to Scott S Zamvil.

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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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