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Non-myeloablative transplantation of bone marrow expressing self-antigen establishes peripheral tolerance and completely prevents autoimmunity in mice

Gene Therapy volume 19, pages 1075–1084 (2012)Cite this article

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Abstract

Myeloablative transplantation of bone marrow (BM) engineered to express myelin oligodendrocyte glycoprotein (MOG) establishes central intrathymic tolerance and completely prevents MOG-induced experimental autoimmune encephalomyelitis (EAE) in mice. Here we asked whether non-myeloablative transplantation of MOG expressing BM (pMOG-bone marrow transplantation (BMT)) can also provide the same protection. Using stepwise reduction of irradiation doses, 275 cGy irradiation with pMOG-BMT protected 100% of mice from EAE development even with two subsequent re-challenge with MOG. Irradiation doses <275 cGy produced dose-dependent partial protection with significant disease protection still evident at 50 cGy. Splenocytes from 275 cGy recipients proliferated to MOG stimulation in vitro, indicating that MOG-reactive cells are present in the periphery but failed to induce disease. MOG-stimulated splenocytes produced little or no interleukin-17, interferon-γ, granulocyte-monocyte colony stimulating factor and tumor necrosis factor-α compared with EAE control. Adoptive transfer of CD4 T cells from EAE-resistant mice into Rag2−/− mice devoid of MOG expression resulted in MOG-induced EAE in ∼74% of mice. Treatment of EAE-resistant mice with anti-programmed death 1 (PD-1) monoclonal antibody-induced EAE in 67% of mice. We conclude that non-myeloablative transplantation of self-antigen expressing BM induces robust peripheral tolerance that completely prevented EAE development. Our findings implicate clonal anergy and the PD-1 pathway in the maintenance of peripheral tolerance.

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Acknowledgements

This work was supported by funds from the National Health and Medical Research Council of Australia.

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Authors and Affiliations

  1. Department of Medicine, Autoimmunity Laboratory, Centre for Inflammatory Diseases, Southern Clinical School, Monash University, Clayton, Victoria, Australia,

    H Hosseini, D Y Oh, S T Chan, X T Chen, B-H Toh & J Chan

  2. Department of Immunology, Central Clinical School, Monash University, Prahran, Victoria, Australia

    Z Nasa & F Alderuccio

  3. Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan

    H Yagita

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  1. H Hosseini
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Hosseini, H., Oh, D., Chan, S. et al. Non-myeloablative transplantation of bone marrow expressing self-antigen establishes peripheral tolerance and completely prevents autoimmunity in mice. Gene Ther 19, 1075–1084 (2012). https://doi.org/10.1038/gt.2011.179

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