Mucosal Immunology Section, NIDCR, NIH, Bethesda, MD 20892, USA.
Mucosal Immunology Section, NIDCR, NIH, Bethesda, MD 20892, USA; Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, China.
EBioMedicine. 2019 Jun;44:50-59. doi: 10.1016/j.ebiom.2019.05.005. Epub 2019 May 13.
Clinical trials on multiple sclerosis with repeated injections of monoclonal antibodies depleting CD4 T cells have not resulted in much success as a disease therapy. Here, we developed an immunotherapy for EAE in mice by combining a transient depletion of T cells together with the administration of neuron derived peptides.
EAE was induced in SJL and C57BL/6 mice, by proteolipid protein peptide PLP (pPLP) and myelin-oligodendrocyte glycoprotein MOG (pMOG) peptides, respectively. Anti-CD4 and anti-CD8 antibody were injected intraperitoneally before or after peptide immunization. EAE scores were evaluated and histology data from brain and spinal cord were analyzed. Splenocytes were isolated and CD4, CD4CD25 and CD4CD25 T cells were purified and cultured in the presence of either specific peptides or anti-CD3 antibody and proliferation of T cells as well as cytokines in supernatant were assessed.
This experimental treatment exhibited therapeutic effects on mice with established EAE in pPLP-susceptible SJL mice and pMOG-susceptible C57BL/6 mice. Mechanistically, we revealed that antibody-induced apoptotic T cells triggered macrophages to produce TGFβ, and together with administered auto-antigenic peptides, generated antigen-specific Foxp3 regulatory T cells (T cells) in vivo.
We successfully developed a specific immunotherapy to EAE by generating autoantigen-specific T cells. These findings have overcome the drawbacks of long and repeated depletion of CD4 T cells, but also obtained long-term immune tolerance, which should have clinical implications for the development of a new effective therapy for multiple sclerosis. FUND: This research was supported by the Intramural Research Program of the NIH, NIDCR.
多发性硬化症的临床试验中，多次注射耗竭 CD4 T 细胞的单克隆抗体并没有取得很大的成功。在这里，我们通过结合 T 细胞的短暂耗竭和神经元衍生肽的给药，为 EAE 开发了一种免疫疗法。
通过蛋白脂质蛋白肽 PLP（pPLP）和髓鞘少突胶质细胞糖蛋白 MOG（pMOG）肽分别在 SJL 和 C57BL/6 小鼠中诱导 EAE。在肽免疫之前或之后，通过腹腔内注射抗 CD4 和抗 CD8 抗体。评估 EAE 评分并分析大脑和脊髓的组织学数据。分离脾细胞，并在存在特异性肽或抗 CD3 抗体的情况下培养 CD4、CD4CD25 和 CD4CD25 T 细胞，并评估 T 细胞的增殖和上清液中的细胞因子。
这种实验性治疗对 pPLP 易感 SJL 小鼠和 pMOG 易感 C57BL/6 小鼠的已建立 EAE 小鼠具有治疗作用。从机制上讲，我们发现抗体诱导的凋亡 T 细胞触发巨噬细胞产生 TGFβ，并与给予的自身抗原肽一起，在体内产生抗原特异性 Foxp3 调节性 T 细胞（T 细胞）。
我们通过生成自身抗原特异性 T 细胞成功开发了针对 EAE 的特定免疫疗法。这些发现克服了长期和重复耗竭 CD4 T 细胞的缺点，但也获得了长期的免疫耐受，这应该对开发多发性硬化症的新有效疗法具有临床意义。
本研究得到 NIH、NIDCR 内部研究计划的支持。
