干細胞治療自身免疫性疾病

1、UB-MSC: the new gold standard to treat several human diseases, especially autoimmune diseasesInstitute of Clinical Medicine, Renmin Hospital, Hubei University of MedicineJunming Tang2015.81.Outline一、Definition二、Characteristics三、Classification四、Pathogenesis五、Traditional therapy六、Biotherapy(antibody、v

2、accine、gene therapy ) 七、Cell therapy(DC、HSC、MSC)2.一、Definition Autoimmunity refer to the immune responses to self cells or self components.Autoimmune disease refer to the disease state resulted from immune responses directed against self cells or self components. 3.二、Characteristics Autoimmune antib

3、ody and (or) autoreactive T lymphocyte can be detected.Autoimmune antibody and (or) autoreactive T lymphocyte mediate immune response which lead to damage or functional disturbanceThe turnover of pathogenetic condition relate with autoimmune response intensityRecurrent attacks and chronic 4.三、Classi

4、ficationOrgan-specific autoimmune disease Graves disease、insulin-dependent diabetes mellitusSystemic autoimmune disease systemic lupus erythematosus5.四、PathogenesisAutoimmune antibodyDisfunction immunologic system(autoreactive T lymphocyte)Genetics and endocrine6.Examples of Human Autoimmune Disease

5、s with Possible Molecular Mimicry as a Mechanism Clin Rev Allergy Immunol. 2012; 42(1): 102C117.類別病名自身抗原非器官特異性系統性紅斑狼瘡胞核成分（DNA,DNP,RNP,Sm）類風濕性關節(jié)炎變性IgG,類風濕相關的核抗原干燥綜合征細胞核（SS-A,SS-B）,唾液腺管胞漿線粒體,微粒體,紅細胞,血小板混合性結締組織病細胞核（RNP）器官特異性喬本甲狀腺炎甲狀腺球蛋白、微粒體Graves病甲狀腺細胞表面THS受體Addison病腎上腺皮質細胞幼年型糖尿病胰島細胞萎縮性胃炎胃壁細胞潰瘍性結腸炎結腸上皮

6、細胞原發(fā)性膽汁性肝硬化膽小管細胞、線粒體重癥肌無力乙酰膽堿受體自身免疫性溶血性貧血紅細胞特發(fā)性血小板減少性紫癜血小板常見自身免疫病 8.五、Traditional therapyGeneral therapyCortisoneImmune inhibitorsOthers 9.六、BiotherapyAntibodyVaccinePharmaceutical Biotechnology 2012, 19( 4) : 364 368. ChineseJournalofNewDrugs2011, 20(8)10.How to better solve the suffering of patien

7、tsNew ways11.七、Gene and Cell therapyDC、NK、CIK、B、T、LAKStem cells(HSC、MSC.）12.八、Stem Cell therapy for AID1.Definition & Historic landmarks 2.Cell types: MSC origin and 3.Cell harvest, culture and store4.Delivery method5.Comparative Evaluation6.Animal experimental7.Mechanism8. Clinical experimental 9.C

8、onclusion13.1.Stem cells14.15Historic landmarks in the field of stem cell biologyCirc Res. 2014;114:21-27.)15.2.Cell types1616.MSC: origin and biological traits/library/images/in-vivo-mesenchymal-stem-cells-originCsar Nombela-Arrieta,Nature Reviews Molecular Cell Biology 12, 126-131 (2011)SynoviumCa

9、rtilageDental pulpBone marrow Kidney Pancreas Adipose tissue Muscle Brain liverTonsilPlacentaUmbilical CordThymusPericytesAmniotic fluid17.3.Isolation, culture store of mesenchymal stem cells from Whartons jelly J. Biomedical Science and Engineering, 2012, 5, 580-586 Cryobiology. 2014 Jun;68(3):467-

10、72. Current Stem Cell Research & Therapy, 2013, 8, 144-15518.4.Delivery methodsPMID: 2606803019.5.Comparative Evaluation of different MSCsJ Immunol Res. 2015:394917. 20.The advantages of UB-MSCsStem Cells International, 2013,24613421.Table 1: Phenotypic profile of WJ-MSCs compared to MSCs from other

11、 sources22.Table 2: Transcriptomic profile of WJ-MSCs compared to MSCs from other sources23.Table 2: Transcriptomic profile of WJ-MSCs compared to MSCs from other sources24.The differentiation advantages of WJ-MSCs compared to MSCs from other sourcesTissue Eng Part B Rev. 2014 Oct;20(5):523-44. 25.B

12、etter: autologous/allogenic?Allogenic healthy BM-MSC, UB-MSCCellular Immunology 293 (2015) 11312126.Summary . 1.Umbilical cord derived MSCs are more primitive, proliferative, regenerative, homing and immuno-suppressive than their adult counterparts2.Healthy UB-MSC is better than MSC from patient-sel

13、f27.6.Preclinical Efficacy and Mechanisms of Mesenchymal Stem Cells in Animal Models of Autoimmune DiseasesImmune Network 2014;14(2):81-8828.7.Mesenchymal stem cell immunosuppression of innate/adaptive immune cellsWorld J Stem Cells 2014; 6(5): 526-53929.Differential toll-like receptor stimulation a

14、ffects mesenchymal stem cell immune-modulation 30.SummaryImmunosuppression31.Permit for application of UB-MSC in human AIDCellStemCell 17,July2,201532.8.Clinical trails: Stem cell for AID33.Clinical trials (registered as of Aug.8 2015 ) using HSChaematologica | 2010; 95(2):184-193.34.Clinical trials

15、 (registered ) using MSC During HSC transplantationMaria Ester Bernardo, Immunology Letters,Available online 25 June 2015Experimental & Molecular Medicine (2013) 45, e235.Clinical trials (registered as of Aug.8 2015 ) using MSCCellStemCell 17,July2,2015Annu. Rev. Immunol. 2013. 31:28531636.Clinical

16、trials (registered as of Aug.8 2015 ) using UB-MSC for AID37.Safety and feasibilityWoodworthand Furst Arthritis Research&Therapy 2014, 16:11338.Risks and Rewards Stem Cells Dev 2015 Jun.PMID: 2606803039.Effects: CausesEg: Mesenchymal stem cells can induce neuron recovery in multiple sclerosisAmerica

17、n Journal of Occupational Therapy, 2014,68, 2732.Cellular Immunology 293 (2015) 113121Stem Cell Rev. 2012;8(3):940-52.40.Summary: FDA permit for UB-MSC多系統硬化風濕性關節(jié)炎I型糖尿病系統性紅斑狼瘡狼瘡腎炎肝夏科氏肝硬變自身免疫性肝炎IgA腎病克隆病色素性視網膜炎血栓閉塞性脈管炎進行性面部偏側萎縮41.Take-home messagesUB-MSC: the new gold standard to treat several human di

18、seases, especially autoimmune and neurodegenerative diseases42.431 Tang JM, Luo B, Xiao JH, Lv YX, Li XL, Zhao JH, Zheng F, Zhang L, Chen L, Yang JY, Guo LY, Wang L, Yan YW, Pan YM, Wang JN, Li DS, Wan Y, Chen SY. VEGF-A promotes cardiac stem cell engraftment and myocardial repair in the infarcted h

19、eart.Int J Cardiol. 2015;183:221-31.2. Xie WB, Li Z, Shi N, Guo X, Tang J, Ju W, Han J, Liu T, Bottinger EP, Chai Y, Jose PA, Chen SY.Smad2 and myocardin-related transcription factor B cooperatively regulate vascular smooth muscle differentiation from neural crest cells.Circ Res. 2013;113(8):e76-86.

20、 3. Tang JM, Wang JN, Zhang L, Zheng F, Yang JY, Kong X, Guo LY, Chen L, Huang YZ, Wan Y, Chen SY.VEGF/SDF-1 promotes cardiac stem cell mobilization and myocardial repair in the infarcted heart.Cardiovasc Res. 2011; 91(3):402-11. 4. Tang J, Wang J, Yang J, Kong X, Zheng F, Guo L, Zhang L, Huang Y. M

21、esenchymal stem cells over-expressing SDF-1 promote angiogenesis and improve heart function in experimental myocardial infarction in rats. Eur J Cardiothorac Surg. 2009, 36(4):644-50. PMID: 19524448.5.Tang J, Xie Q, Pan G, Wang J, Wang M. Mesenchymal stem cells participate in angiogenesis and improv

22、e heart function in rat model of myocardial ischemia with reperfusion. Eur J Cardiothorac Surg. 2006; 30(2):353-61.6.Tang J, Wang J, Zheng F, Yang J, Kong X, Guo L, Zhang L, Huang Y. Vascular endothelial growth factor promotes cardiac stem cell migration via the PI3K/Akt pathway. Experimental Cell R

23、esearch.2009, 315(20):3521-3531. 7. Tang J, Wang J, Kong X, Zheng F, Yang J, Guo L, Zhang L, Huang Y. Mesenchymal stem cells modified with stromal cell-derived factor 1 improve remodeling via paracrine activation of hepatocyte growth factor in a rat model of myocardial infarction. Moleculars and Cel

24、ls. 2010,29(1):1-10.8.Tang J, Wang J, Kong X, Yang J, Zheng F, Guo L, Zhang L, Huang Y. Adenovirus-mediated stromal cell-derived- factor-1 alpha gene transfer improves cardiac structure and function after experimental myocardial infarction through angiogenic and antifibrotic actions. Molecular Biolo

25、gy Reports. Mol Biol Rep. 2010; 37(4):1957-69.9. Tang J, Wang J, Zheng F, Kong X, Guo L, Yang J, Zhang L, Huang Y.Combination of chemokine and angiogenic factor genes and mesenchymal stem cells could enhance angiogenesis and improve cardiac function after acute myocardial infarction in rats. Mol Cel

26、l Biochem. 2010; 339(1-2):107-18.10. Tang JM, Yuan J, Li Q, Wang JN, Kong X, Zheng F, Zhang L, Chen L, Guo LY, Huang YH, Yang JY, Chen SY.Acetylcholine induces mesenchymal stem cell migration via Ca2+ /PKC/ERK1/2 signal pathway.J Cell Biochem. 2012;113(8):2704-13.11. Zhang L, Dong XW, Wang JN, Tang

27、JM, Yang JY, Guo LY, Zheng F, Kong X, Huang YZ, Chen SY.PEP-1-CAT-transduced mesenchymal stem cells acquire an enhanced viability and promote ischemia-induced angiogenesis.PLoS One. 2012;7(12):e52537Publication .Publication 446.Tang J, Wang J, Zheng F, Yang J, Kong X, Guo L, Zhang L, Huang Y. Vascul

28、ar endothelial growth factor promotes cardiac stem cell migration via the PI3K/Akt pathway. Experimental Cell Research.2009, 315(20):3521-3531. 7. Tang J, Wang J, Kong X, Zheng F, Yang J, Guo L, Zhang L, Huang Y. Mesenchymal stem cells modified with stromal cell-derived factor 1 improve remodeling via paracrine activation of hepatocyte growth factor in a rat model of myocardial infarction. Moleculars and Cells. 2010,29(1):1-10.8.Tang J, Wang J, Kong X, Yang J, Zheng F, Guo L, Zhang L, Huang Y. Adenovirus-mediated stromal cell-derived- factor-1 alpha ge