Autoimmunity Laboratory, Centre for Inflammatory Diseases, Department of Medicine, Southern Clinical School, Monash University, Clayton, Victoria, Australia.
Gene Ther. 2012 Nov;19(11):1075-84. doi: 10.1038/gt.2011.179. Epub 2011 Nov 10.
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.
骨髓（BM）经髓过氧化物酶（MOG）表达工程改造后进行骨髓移植可诱导中枢性胸腺内耐受，并完全预防小鼠的髓鞘少突胶质细胞糖蛋白（MOG）诱导的实验性自身免疫性脑脊髓炎（EAE）。在此，我们询问表达 MOG 的骨髓（pMOG-骨髓移植（BMT））的非清髓性移植是否也能提供相同的保护。通过逐步降低照射剂量，用 275 cGy 照射+pMOG-BMT 可保护 100%的小鼠免受 EAE 发展的影响，即使在随后两次用 MOG 再挑战也是如此。照射剂量<275 cGy 产生剂量依赖性的部分保护，在 50 cGy 时仍有明显的疾病保护作用。275 cGy 受者的脾细胞在体外对 MOG 刺激增殖，表明外周存在 MOG 反应性细胞，但未能引起疾病。与 EAE 对照组相比，MOG 刺激的脾细胞产生的白细胞介素-17、干扰素-γ、粒细胞-巨噬细胞集落刺激因子和肿瘤坏死因子-α很少或没有。从 EAE 抗性小鼠中过继转移 CD4 T 细胞到缺乏 MOG 表达的 Rag2(-/-) 小鼠中，导致约 74%的小鼠发生 MOG 诱导的 EAE。用抗程序性死亡 1（PD-1）单克隆抗体治疗 EAE 抗性小鼠，导致 67%的小鼠发生 EAE。我们得出结论，表达自身抗原的 BM 的非清髓性移植诱导了强大的外周耐受，完全预防了 EAE 的发展。我们的发现表明克隆无能和 PD-1 途径在维持外周耐受中起作用。
