We studied safety and clinical efficacy of transplantation of autologous bone marrow cell in complex therapy of 158 patients with chronic hepatitis and cirrhosis of the liver. The efficiency of cell therapy was assessed in 12 months after single injection of the cells. The positive response (alleviation of liver cirrhosis or stabilization of the pathological process) was observed in 70% cases. The efficacy of therapy correlated with the severity and etiology of the disease and was maximum in patients with Child-Pugh class A (in 82.5% cases) and class B liver cirrhosis (in 79% cases); in patients with class C liver cirrhosis, the positive response was achieved in 42.5% cases. In 39 patients, ultrasonic examination performed in 3 years after transplantation revealed no focal lesions or ectopic ossification foci.
Научно-исследовательский институт фундаментальной и клинической иммунологии, г. Новосибирск, Россия Резюме. Цитокины играют важную роль в патогенезе цирроза печени (ЦП), детерминируя тяжесть заболевания, развитие печеночных и внепеченочных осложнений. Целью исследования являлся мультиплексный анализ 26 цитокинов, секретируемых клетками крови больных ЦП (n = 20) с учетом стадии (класс А по Child-Pugh, n = 13 и класс В+С, n = 7) и этиологии заболевания (вирусный ЦП, n = 12 и ЦП невирусной этиологии, n = 8). Группу контроля составили 10 здоровых доноров крови. Цитокин-секреторную функцию клеток оценивали в 24-часовых культурах как на уровне спонтанной продукции, так и в ответ на стимуляцию бактериальным эндотоксином (ЛПС). При анализе цитокинов, вовлеченных в патогенез воспалительного процесса, было выделено 4 функциональные группы: про
Liver cirrhosis (LC) is a serious problem with respect to drug therapy. Certain promises are associated with development of stem cell-based technologies, in particular, mesenchymal stromal cells (MSCs). Over recent years, a significant interest was drawn to the usage of MSCs isolated from adipose tissue, which have a number of advantages over bone marrow MSCs. The aim of this study was to evaluate safety and tolerability of transplantation of autologous MSCs derived from adipose tissue (lipoaspirate) when treating the patients with LC of different origin. The study group consisted of 12 patients (4 men and 8 women), aged 33 to 67 years. In six patients, development of LC was due to viral hepatitis; in other subjects it was caused by non-viral factors, including toxic effects (n = 3), primary biliary cirrhosis (n = 2) and cryptogenic cirrhosis (n = 1). The LC severity assessed by the Child-Pugh scale corresponded to class A (6 cases) or class B (6 patients). The MELD scores varied from 8 to 11. All patients were injected once with autologous MSCs (a mean of 12.94 106, 11.3 to 16.0 106) obtained by culturing the lipoaspirate cells for 14 days. Lipoaspiration and injection of MSCs were not accompanied by development of side effects, or serious adverse events. Analysis of clinical efficacy, carried out 6-12 months after therapy, made it possible to distinguish two subgroups: responders to the therapy (subgroup 1, n = 6) and non-responders (subgroup 2, n = 6). In subgroup 1, the MELD score was found to be decreased in 4 cases, and did not change in 2 patients. In contrast, the MELD score increased in the patients from subgroup 2. Both subgroups did not differ in etiology and severity of LC, or concomitant pathology (COVID-19). Positive dynamics in subgroup 1 was revealed for the signs of hepatocellular insufficiency (n = 1), cytolysis (n = 2) and cholestasis (n = 1). In two patients with MELD score stabilization, the scores reached the reference values. After MSC therapy, the majority of patients (8/12) underwent a new coronavirus infection, and the COVID incidence rate was similar in groups with or without response to MSC therapy (4 patients in each group). The results of the study suggest the safety of using MSCs isolated from the adipose tissue of patients with liver cirrhosis, and the perspectives of such approach in order to stabilize or improve liver function.
In the present study, we used multicolor flow cytometry assay to measure the numbers of various myeloid suppressor cell subpopulations (Lin-HLA-DR-CD33+, Lin-HLA-DR-CD33+CD66b+, and CD14+HLA-DRlow/-) in peripheral blood of 51 participants, including 33 patients with viral- and 1 8 patients with «nonviral» (alcoholic or biliary/autoimmune) liver cirrhosis. Patients in both groups had increased proportions of Lin-HLA-DR-CD33+, Lin-HLA-DR-CD33+CD66b+, and CD 14+HLA-DRlow/-cells which levels did not depend on the type and replication of the virus in viral liver cirrhosis. In viral liver cirrhosis, the relative numbers of Lin-HLA-DR-CD33+cells directly correlated with the albumin levels (Rs=0.45; p=0.029). In «nonviral» group an inverse relationship was found between these indicators (Rs = -0.56; p=0.02), in addition the proportion of Lin-HLA-DR-CD33+and CD14+HLA-DRlow/-cells directly correlated with disease severity scores (Child-Pugh and MELD) direct correlation of the proportion of Lin-HLA-DR-CD33+and CD14+HLA-DRlow/-cells with the disease severity scores (Child-Pugh and MELD). Comparison of the initial content of myeloid suppressors with the response to complex therapy (that included autologous bone marrow-derived cell transplantation), showed that in viral liver cirrhosis, the proportion of Lin-HLA-DR-CD33+cells was characterized by a prognostic significance and, at values
Viral hepatitis remains the most common cause of liver cirrhosis (LC). Monocytes, capable of migrating to the liver and participating in inflammation and fibrogenesis, play an important role in the pathogenesis of LC, which is confirmed by the association of certain monocyte subpopulations with the disease severity and mortality in alcoholic and biliary LC. However, in viral LC the clinical and prognostic relevance of monocytes has been less investigated. This study aimed to investigate the disturbances of circulating monocytes including classical (CD14 ++CD16−, cMo), intermediate (CD14++CD16+, iMo) and non-classical monocytes (CD14+CD16++, nMo) in patients with viral LC, as well as the correlation of these cells with viral characteristics, LC severity and the progression of the disease 12 months following complex therapy. It was revealed a significant increase in iMo and nMo, a tendency to decrease of cMo, and a two-fold reduction in cMo/iMo ratio in patients with viral LC compared to healthy donors. These changes in monocyte pattern did not depend on the type of virus (HCV against HBV/HDV) and virus replication (replication against the integrative phase), but were associated with the LC severity. The proportion of iMo was positively correlated with laboratory indicators of liver damage, Chaild-Pugh (RS=0.57; P=0.001) and MELD score (RS=0.41; P=0.033). ROC analysis showed that the cMo/iMo ratio at the values of 9.5 allowed to predict the risk of LC progression with a sensitivity of 83.3% and a specificity of 76.2%. Of note, patients with alcoholic or biliary/autoimmune LC in comparison groups also demonstrated increased frequencies in iMo and nMo and decreased cMo/iMo ratio. However, in this case, the LC severity was negatively correlated with CD16+monocytes, in particular, with the iMo and nMo subset, respectively, in alcoholic and biliary LC, evidencing the protective role of these subpopulations. Conclusion: in viral LC the changes in circulating monocytes towards an increase in iMO and nMo and decrease in cMo are not associated with the virus type and replication; in contrast to the alcoholic and biliary/autoimmune LC, the proportion of iMo directly correlates with the indicators of liver damage and LC severity; cMo/iMo ratio is a biomarker of therapy response/disease progression.
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