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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This work was supported by funds from the National Health and Medical Research Council of Australia.
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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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DOI: https://doi.org/10.1038/gt.2011.179