医学免疫学课件：MSC在多发性硬化症中的应用

1、MSC在多发性硬化症中的应用目录ContentPart One多发性硬化症简介Part Two基于MSC的免疫治疗Part Three临床治疗与展望多发性硬化症Part One多发性硬化症简介Part One点击此处添加标题Multiple Sclerosis, MS年轻患者非创伤性神经性残疾首要原因常见于20-40岁，女性多发自身免疫病可能与遗传、感染有所关联CNS脱髓鞘多发性硬化症症状Part One感觉/运动症状（前三，uptodate）肢体感觉障碍视觉问题运动功能障碍Reproduced with permission from: Richards RG, Sampson FC, Be

2、ard SM, Tappenden P. A review of the natural history and epidemiology of multiple sclerosis: implications for resource allocation and health economic models. Health Technol Assess 2002; 6:1. Copyright 2002 Queens Printer and Controller of HMSO.多发性硬化症分类Part One多发性硬化症机制Part One激活T细胞突破BBB（4-integrin/VL

3、A-4 VCAM-1，细胞黏附因子）效应T细胞，B细胞，补体等促进特异性免疫Th1等和小胶质细胞分泌细胞因子（如OPN，IL-23，IFN-等）主要是Th1/Th2和Th17/Treg抑制进入：IFN-，那他珠单抗基于MSC的免疫治疗Part Two实验性自身免疫性脑脊髓炎（EAE）动物模型1. 以特异性致敏的CD4+T细胞介导为主的自身免疫性疾病2.以中枢神经系统内，小血管周围出现单核细胞浸润，及髓鞘脱失为特征3.人类多发性硬化（MS）的理想动物模型.4. 多用大鼠制备EAE。1998年建立了猴的EAE模型。不同之处EAE为自限性发病原不同症状EAE：多于脊髓发病，多为经典的软瘫MS：炎症部

4、位多在脑部，多种临床症状间充质干细胞Part Two三条判断标准贴壁生长细胞表面表达CD105、CD73和CD90（95%），不表达CD45、CD34等造血干细胞和内皮细胞的表面标志（2%）适宜条件可以诱导分化为成骨细胞、成脂细胞和成软骨细胞优点：低免疫原性不表达MHC II类分子，MHC I类中/低等程度表达免疫调节作用（抗炎性反应）患者可自体移植伦理问题小排斥反应低致瘤性低MSC的免疫调节Part Two/ky/kyjz/201410/t20141027_4231535.shtmlMSC的免疫调节2002年Bartholomew等发现归巢特性，向炎症区域炎症微环境的调节免疫可塑性主要调节方

5、式Cell-cell contact（Th1，效应T细胞细胞毒性）分泌细胞因子MicrovesicleMSC的免疫调节Part Two点击此处添加标题标题数字等都可以通过点击和重新输入进行更改，顶部“开始”面板中可以对字体、字号、颜色、行距等进行修改。建议正文8-14号字，1.3倍字间距。标题数字等都可以通过点击和重新输入进行更改，顶部“开始”面板中可以对字体、字号、颜色、行距等进行修改。主要调节方式Cell-cell contact分泌细胞因子Microvesicle调节网络复杂多样举两个例子Gharibi, Tohid, et al. Immunomodulatory characteri

6、stics of mesenchymal stem cells and their role in the treatment of Multiple Sclerosis. Cellular immunology 293.2 (2015): 113-121.调控网络的复杂性Part TwoIL-6造血和炎症中B的成熟，Treg抑制，向Th17分化M1（IFN-，TNF-等） M2，modifier作用等多效性Melief S M, Geutskens S B, Fibbe W E, et al. Multipotent stromal cells skew monocytes towards

7、an anti-inflammatory interleukin-10-producing phenotype by production of interleukin-6.J. Haematologica, 2013, 98(6):888-95.Hunter C A, Jones S A. IL-6 as a keystone cytokine in health and disease.J. Nature Immunology, 2015, 16(5):448-57.Part TwoWang X, Kimbrel E A, Ijichi K, et al. Human ESC-derive

8、d MSCs outperform bone marrow MSCs in the treatment of an EAE model of multiple sclerosis.J. Stem Cell Reports, 2014, 3(1):115130.调控网络的复杂性IL-6造血和炎症中B的成熟，DC活化，Treg抑制，向Th17分化M1（IFN-，TNF-等） M2，modifier作用等eg. MSC+anti-IL-6-Ag调控网络的复杂性Part TwoTh9 (2008年鉴定出)很多证据表示与Th17拮抗发作时CSF IL-9水平低，泼尼松龙治疗时高107 RRMS 患者实验

9、， CSF IL-9水平与炎症、神经元退变程度负相关然体外实验分化的Th9刺激EAE&外周神经炎多效性 + 多方面影响 复杂性（&不一致的试验结果）不断试验调节网络不断扩大Elyaman W, Khoury S J. Th9 cells in the pathogenesis of EAE and multiple sclerosisJ. Seminars in Immunopathology, 2016:1-9.Laranjeira P, Pedrosa M, Pedreiro S, et al. Effect of human bone marrow mesenchymal stromal

10、 cells on cytokine production by peripheral blood naive, memory, and effector T cellsJ. Stem Cell Research & Therapy, 2015, 6(1):3-3.MSC的神经保护再生Part Two神经保护CNS慢性炎症会主动募集MSCMSC能分泌BDNF（脑源性神经营养因子）和NGF（神经生长因子）OPC（少突胶质前体细胞）&神经干细胞神经分化体外顺利体内转化：现有实验结果转分化能力有限大多数MSC抑制利用的是免疫调节功能其他利用方式Part Two基因工程Eg促进MSC过表达IFN-，I

11、L-4，IL-10的报告Microvesicle的应用Eg.2015年利用MV转运RNA，刺激MSC产生HGF，使肾小管细胞脱分化、生长HGF也有报道在MSC治疗MS/EAE中抗炎药物联合作用/药物预处理Eg. 2016年 法舒地尔、雷帕霉素的共同作用研究用NT-3（神经营养因子3）和视黄酸（RA）临床治疗与展望Part Three实际临床效果Part ThreeRossman I, Cohen J A. Cell-Based Therapeutic Strategies in Multiple SclerosisJ. European Neurological Review, 2014, 9

12、(1):37-43.Eg. 第一个为例，12个月鞘内MSC移植在进展型MS中安全，可耐受无集体EDSS改变12个月里MRI下损伤无变化为（68.2%）12个月里MRI下损伤增大为（27.3%）造血干细胞的免疫重建治疗Part ThreeAtkins H L, Bowman M, Allan D, et al. Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial

13、.J. Lancet, 2016, 388(10044):576-585.免疫消除所用：白消安，环磷酰胺和兔抗胸腺细胞球蛋白三年无复发率69.6%8名7年多无复发治疗前平均1.2年复发一次早期患者，已残疾无效小结与展望Part Three1. MSC对MS总体效果显著 具体调控机制有待明确2. 与MSC共培养后的免疫细胞移植实验还较少3. EAE与人体MS真实情况的差距4. MSC应用方法需要更大胆的想象参考文献Part FourXiao, Juan, et al. Mesenchymal stem cells and induced pluripotent stem cells as the

14、rapies for multiple sclerosis. International journal of molecular sciences 16.5 (2015): 9283-9302.Gharibi, Tohid, et al. Immunomodulatory characteristics of mesenchymal stem cells and their role in the treatment of Multiple Sclerosis. Cellular immunology 293.2 (2015): 113-121.Liu, Zhou, et al. Elect

15、roacupuncture Promotes the Differentiation of Transplanted Bone Marrow Mesenchymal Stem Cells Preinduced With Neurotrophin-3 and Retinoic Acid Into Oligodendrocyte-Like Cells in Demyelinated Spinal Cord of Rats. Cell transplantation 24.7 (2015): 1265-1281.Togha, Mansoureh, et al. Rapamycin Augments

16、Immunomodulatory Properties of Bone Marrow-Derived Mesenchymal Stem Cells in Experimental Autoimmune Encephalomyelitis. Molecular neurobiology (2016): 1-13.5. Harris V K, Vyshkina T, Sadiq S A. Clinical safety of intrathecal administration of mesenchymal stromal cell-derived neural progenitors in mu

17、ltiple sclerosis.J. Cytotherapy, 2016, 18(12):14761482.6. Rossman I, Cohen J A. Cell-Based Therapeutic Strategies in Multiple SclerosisJ. European Neurological Review, 2014, 9(1):37-43.8. Atkins H L, Bowman M, Allan D, et al. Immunoablation and autologous haemopoietic stem-cell transplantation for a

18、ggressive multiple sclerosis: a multicentre single-group phase 2 trial.J. Lancet, 2016, 388(10044):576-585.9. Ju, G.Q.; Cheng, J.; Zhong, L.; Wu, S.; Zou, X.Y.; Zhang, G.Y.; Gu, D.; Miao, S.; Zhu, Y.J.; Sun, J.; et al. Microvesicles derived from human umbilical cord mesenchymal stem cells facilitate tubular epithelial cell dedifferentiation and growth via hepatocyte growth factor induction. PLoS ONE 2015, 10, e012153410. Elyaman W, Khoury S J. Th9 cells in the pathogenesis of EAE and multiple sclerosisJ. Seminars in Immunopathology, 2016:1-9.11. Hunter C A, Jones S A. IL