原发性胆汁性肝硬化的免疫发病机制和人脐带间充质干细胞治疗的安全性及有效性的研究
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摘要
长期以来，关于原发性胆汁性肝硬化（PBC）患者自身抗体谱与疾病进展程度的相关性了解不够清楚。此外，患者血液中和肝内浸润的T细胞参与了PBC的病理损伤过程，失衡的T细胞导致自身反应性T细胞大量增殖引起PBC患者的免疫紊乱，但是肝硬化不同阶段PBC患者T细胞与临床指标的相关性研究目前不够深入。熊去氧胆酸（UDCA）是目前唯一公认的治疗PBC的药物。UDCA治疗应答的患者可有效延缓疾病进展，延长生存时间。然而，超过40％的患者对UDCA治疗表现为不完全应答，因此，对这些不完全应答的患者在临床上急需发展有效的治疗方法。
研究目的
1.观察自身抗体谱与PBC患者临床表现及疾病进展的相关性。
2.分析PBC患者与健康人以及PBC患者不同分组间T细胞亚群变化，并进一步分析肝硬化不同阶段PBC患者T细胞亚群与临床指标的相关性。
3.初步研究人脐带间充质干细胞（UC-MSCs）治疗PBC的临床安全性及有效性。
研究内容和方法
1.通过间接免疫荧光法检测外周血自身抗体(ANA、AMA)，免疫印迹法检测AMA-M2、anti-PML、anti-gp210、anti-Sp100、anti-BPO、anti-52KD，我们对123例PBC患者进行了自身抗体检测，并查阅患者相关临床资料、实验室及B超、影像学检查资料。
2.采用流式细胞染色技术，我们对49例肝硬化不同阶段PBC患者外周血T淋巴细胞亚群进行频率检测。
3.利用人脐带间充质干细胞（UC-MSCs）外周静脉回输给7例对UDCA不完全应答的PBC患者，观察UC-MSCs治疗PBC的安全性及初步有效性。
研究结果
1.通过比较肝硬化期与非肝硬化期患者血清中ANA、AMA、AMA-M2、anti-PML、anti-SP100、anti-52KD阳性检测率，我们发现差异均无统计学意义。anti-gp210阳性率肝硬化组显著高于非肝硬化组。anti-gp210阳性的PBC患者转氨酶、胆红素及碱性磷酸酶水平显著高于anti-gp210阴性患者，而胆碱酯酶及白蛋白水平较之偏低。
2.与健康人相比，PBC患者外周CD4+T细胞频率升高, CD8+T细胞频率降低，CD4/CD8比例上升，且失代偿期PBC患者比值明显高于代偿期；CD8+T细胞频率与ALB、CHE、PA显著正相关，而与PT和INR显著负相关；CD4/CD8T细胞的比值与PT和INR显著正相关，与ALB、PA和CHE显著负相关。Th1细胞亚群频率和CHE、自身抗体数目呈显著正相关，而与TBA、PT、INR显著负相关。Th17细胞亚群频率和自身抗体数目呈显著正相关，与ALB、ALB/GLO呈显著负相关。
3.UC-MSCs回输治疗PBC后病人没有发生近期及远期不良反应；UC-MSCs输注可显著降低血清ALP水平，且在48周的随访期间的MRS保持稳定，同时可以改善PBC患者的生活质量，减轻疲劳和皮肤瘙痒症状。UC-MSCs回输后某些患者的肝功能和临床症状均改善。
结论
1.本研究发现：与anti-gp210阴性的患者相比，anti-gp210阳性的患者有更严重的胆汁淤积和肝功能损害，anti-gp210对疾病的进展有一定的预测价值。
2.PBC患者外周CD8+T细胞的数量显著减少，特别是失代偿期阶段患者，可能促进了疾病的进展。此外升高的外周CD4+T细胞很可能间接破坏了肝脏的合成功能。Th17细胞可能影响了PBC患者肝脏的蛋白合成功能。
3.对于UDCA治疗不完全应答的PBC患者，通过外周静脉输注UC-MSCs是安全和可行的。
BACKGROUND
Previous studies on the relationship between autoantibody profile andprogression of primary biliary cirrhosis remain unknown. In addition, circulating andhepatic T cells are often involved in the development of primary biliary cirrhosis,skewed frequency as well as the ratio of T cells may lead to proliferation ofautoreactive of T cells and immune disorder in PBC patients, but the relationshipbetween T cells of PBC patients and the clinical markers are elusive. Currently,ursodeoxycholic acid (UDCA) is the only approved first-line drug for PBC patients.Response to UDCA treatment in PBC patients can effectively slow down the diseaseprogression and prolong survival duration, however, more than40%of the patientsare with incomplete response to UDCA therapy. At present, novel effective regimenfor the incomplete response patients is urgently necessary.
AIM
1. To investigate the correlation between autoantibody profile and the clinicalmanifestation as well as the progression of PBC patients.
2. Analyze the change of T cells subsets between PBC and HC and furtherdetect the relationship between the changes and the clinical marker. The changes of Tcells subsets in different stage of cirrhosis PBC patients should also be examined.
3. To conduct a preliminary study on the safety and efficacy of UC-MSCstransfusion in7PBC patients with incomplete response to UDCA.
METHODS
1. Peripheral autoantibodies (ANA, AMA) such as AMA-M2, anti-PML, anti-gp210, anti-Sp100, anti-BPO, anti-Ro-52in123PBC patients were detected byindirect immunofluorescence assay and Western blot. The clinical data, laboratoryparameters, type-B ultrasonic and imaging results of patients were also checked.
2. Flow cytometry were performed to analyze the frequency changes ofperipheral T cells in49PBC patients.
3. Umbilical cord-derived mesenchymal stem cells (UC-MSCs) transfused to7PBC patients with an incomplete response to UDCA and observed the evaluation forthe safety and efficacy of UC-MSCs treatment.
RESULTS
1. Expression of ANA、AMA、AMA-M2、anti-PML、anti-SP100、anti-52KDhad no significant statistically differences between two groups of PBC patients. Theanti-gp210positive patients were significantly higher in cirrhosis PBC patients thanin non-cirrhosis groups. The serum level of aminotransferase, bilirubin and alkalinephosphatase were significantly higher and the serum level of cholinesterase andalbumin levels were lower in anti-gp210positive patients than in negative patients.
2. Compared with HC, the frequencies of peripheral CD4+T cells, the ratio ofCD4/CD8were significantly increased and the frequencies of peripheral CD8+Tcells were significantly decreased in PBC patients. Further studies revealed thatCD4/CD8T-cell ratio were significantly higher in PBC patients in decompensatedstage than in compensated stage; peripheral frequency of CD8+T cell hadsignificantly positive correlation with ALB, CHE, PA, while a significant negativecorrelation with the PT and INR; CD4/CD8ratio had significant positive correlationwith PT and INR but had significant negative correlation with ALB, PA and CHE.Frequency of Th1cells were positively correlated with CHE, the number ofautoantibodies and negative correlated with TBA, PT and INR. Frequency of Th17cell subsets had positive correlation with number of autoantibodies and negativelycorrelated with ALB and ALB/GLO.
3. No obvious recent and long-termed side-effects were found in the patientstreated with UC-MSCs. There was a significant decrease in serum alkaline phosphatase levels in patients transfused with UC-MSCs. The Mayo risk score, aprognostic index, was also stable during the treatment and follow-up period.Transfusion of UC-MSCs could also improved the quality of life of patients withPBC, reduced fatigue and skin itching. In some patients the liver function andclinical symptoms were also improved.
CONCLUSIONS：
1. We found that compared with anti-gp210negative patients, anti-gp210positive patients exhibit severe cholestasis and impaired liver function, anti-gp210might represent a predictive marker for the progression of PBC.
2. Peripheral frequencies of CD8+T cells significantly decreased in patientswith PBC, especially in decompensated stage patients, thus contributing to theprogression of PBC. In addition, elevated peripheral frequencies of CD4+T cells arelikely to indirectly undermine the synthetic function of the liver. Th17cells maynegatively affect the protein synthesis function in patients with PBC.
3. UC-MSCs transfusion is well tolerated in PBC patients who respond onlypartially to UDCA treatment,
研究目的
1.观察自身抗体谱与PBC患者临床表现及疾病进展的相关性。
2.分析PBC患者与健康人以及PBC患者不同分组间T细胞亚群变化，并进一步分析肝硬化不同阶段PBC患者T细胞亚群与临床指标的相关性。
3.初步研究人脐带间充质干细胞（UC-MSCs）治疗PBC的临床安全性及有效性。
研究内容和方法
1.通过间接免疫荧光法检测外周血自身抗体(ANA、AMA)，免疫印迹法检测AMA-M2、anti-PML、anti-gp210、anti-Sp100、anti-BPO、anti-52KD，我们对123例PBC患者进行了自身抗体检测，并查阅患者相关临床资料、实验室及B超、影像学检查资料。
2.采用流式细胞染色技术，我们对49例肝硬化不同阶段PBC患者外周血T淋巴细胞亚群进行频率检测。
3.利用人脐带间充质干细胞（UC-MSCs）外周静脉回输给7例对UDCA不完全应答的PBC患者，观察UC-MSCs治疗PBC的安全性及初步有效性。
研究结果
1.通过比较肝硬化期与非肝硬化期患者血清中ANA、AMA、AMA-M2、anti-PML、anti-SP100、anti-52KD阳性检测率，我们发现差异均无统计学意义。anti-gp210阳性率肝硬化组显著高于非肝硬化组。anti-gp210阳性的PBC患者转氨酶、胆红素及碱性磷酸酶水平显著高于anti-gp210阴性患者，而胆碱酯酶及白蛋白水平较之偏低。
2.与健康人相比，PBC患者外周CD4+T细胞频率升高, CD8+T细胞频率降低，CD4/CD8比例上升，且失代偿期PBC患者比值明显高于代偿期；CD8+T细胞频率与ALB、CHE、PA显著正相关，而与PT和INR显著负相关；CD4/CD8T细胞的比值与PT和INR显著正相关，与ALB、PA和CHE显著负相关。Th1细胞亚群频率和CHE、自身抗体数目呈显著正相关，而与TBA、PT、INR显著负相关。Th17细胞亚群频率和自身抗体数目呈显著正相关，与ALB、ALB/GLO呈显著负相关。
3.UC-MSCs回输治疗PBC后病人没有发生近期及远期不良反应；UC-MSCs输注可显著降低血清ALP水平，且在48周的随访期间的MRS保持稳定，同时可以改善PBC患者的生活质量，减轻疲劳和皮肤瘙痒症状。UC-MSCs回输后某些患者的肝功能和临床症状均改善。
结论
1.本研究发现：与anti-gp210阴性的患者相比，anti-gp210阳性的患者有更严重的胆汁淤积和肝功能损害，anti-gp210对疾病的进展有一定的预测价值。
2.PBC患者外周CD8+T细胞的数量显著减少，特别是失代偿期阶段患者，可能促进了疾病的进展。此外升高的外周CD4+T细胞很可能间接破坏了肝脏的合成功能。Th17细胞可能影响了PBC患者肝脏的蛋白合成功能。
3.对于UDCA治疗不完全应答的PBC患者，通过外周静脉输注UC-MSCs是安全和可行的。
BACKGROUND
Previous studies on the relationship between autoantibody profile andprogression of primary biliary cirrhosis remain unknown. In addition, circulating andhepatic T cells are often involved in the development of primary biliary cirrhosis,skewed frequency as well as the ratio of T cells may lead to proliferation ofautoreactive of T cells and immune disorder in PBC patients, but the relationshipbetween T cells of PBC patients and the clinical markers are elusive. Currently,ursodeoxycholic acid (UDCA) is the only approved first-line drug for PBC patients.Response to UDCA treatment in PBC patients can effectively slow down the diseaseprogression and prolong survival duration, however, more than40%of the patientsare with incomplete response to UDCA therapy. At present, novel effective regimenfor the incomplete response patients is urgently necessary.
AIM
1. To investigate the correlation between autoantibody profile and the clinicalmanifestation as well as the progression of PBC patients.
2. Analyze the change of T cells subsets between PBC and HC and furtherdetect the relationship between the changes and the clinical marker. The changes of Tcells subsets in different stage of cirrhosis PBC patients should also be examined.
3. To conduct a preliminary study on the safety and efficacy of UC-MSCstransfusion in7PBC patients with incomplete response to UDCA.
METHODS
1. Peripheral autoantibodies (ANA, AMA) such as AMA-M2, anti-PML, anti-gp210, anti-Sp100, anti-BPO, anti-Ro-52in123PBC patients were detected byindirect immunofluorescence assay and Western blot. The clinical data, laboratoryparameters, type-B ultrasonic and imaging results of patients were also checked.
2. Flow cytometry were performed to analyze the frequency changes ofperipheral T cells in49PBC patients.
3. Umbilical cord-derived mesenchymal stem cells (UC-MSCs) transfused to7PBC patients with an incomplete response to UDCA and observed the evaluation forthe safety and efficacy of UC-MSCs treatment.
RESULTS
1. Expression of ANA、AMA、AMA-M2、anti-PML、anti-SP100、anti-52KDhad no significant statistically differences between two groups of PBC patients. Theanti-gp210positive patients were significantly higher in cirrhosis PBC patients thanin non-cirrhosis groups. The serum level of aminotransferase, bilirubin and alkalinephosphatase were significantly higher and the serum level of cholinesterase andalbumin levels were lower in anti-gp210positive patients than in negative patients.
2. Compared with HC, the frequencies of peripheral CD4+T cells, the ratio ofCD4/CD8were significantly increased and the frequencies of peripheral CD8+Tcells were significantly decreased in PBC patients. Further studies revealed thatCD4/CD8T-cell ratio were significantly higher in PBC patients in decompensatedstage than in compensated stage; peripheral frequency of CD8+T cell hadsignificantly positive correlation with ALB, CHE, PA, while a significant negativecorrelation with the PT and INR; CD4/CD8ratio had significant positive correlationwith PT and INR but had significant negative correlation with ALB, PA and CHE.Frequency of Th1cells were positively correlated with CHE, the number ofautoantibodies and negative correlated with TBA, PT and INR. Frequency of Th17cell subsets had positive correlation with number of autoantibodies and negativelycorrelated with ALB and ALB/GLO.
3. No obvious recent and long-termed side-effects were found in the patientstreated with UC-MSCs. There was a significant decrease in serum alkaline phosphatase levels in patients transfused with UC-MSCs. The Mayo risk score, aprognostic index, was also stable during the treatment and follow-up period.Transfusion of UC-MSCs could also improved the quality of life of patients withPBC, reduced fatigue and skin itching. In some patients the liver function andclinical symptoms were also improved.
CONCLUSIONS：
1. We found that compared with anti-gp210negative patients, anti-gp210positive patients exhibit severe cholestasis and impaired liver function, anti-gp210might represent a predictive marker for the progression of PBC.
2. Peripheral frequencies of CD8+T cells significantly decreased in patientswith PBC, especially in decompensated stage patients, thus contributing to theprogression of PBC. In addition, elevated peripheral frequencies of CD4+T cells arelikely to indirectly undermine the synthetic function of the liver. Th17cells maynegatively affect the protein synthesis function in patients with PBC.
3. UC-MSCs transfusion is well tolerated in PBC patients who respond onlypartially to UDCA treatment,
引文
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1. Carlo Selmi, Christopher L, Bowlus M, et al. Primary biliary cirrhosis. Lancet,2011,377(9777):1600-09.
2. Braun S, Berg C, Buck S, et al．Catalytic domain of PDC-E2contains epitopesrecognized by antimitochondrial antibodies in primary biliary cirrhosis. World JGastroenteral,2010,16(8):973-81．
3. Lan RY, Cheng C, Lian ZX, et al. Liver-targeted and peripheral blood alterationsof regulatory T cells in primary biliary cirrhosis. Hepatology,2006,43(4):729–37.
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