Allogeneic Bone Marrow Mesenchymal Stem Cell Transplantation In Refractory Primary Biliary Cirrhosis

Part One Clinical analysis of refractory primary biliary cirrhosisObject To describe the clinical characters of refractory primary biliary cirrhosis, and to investigate the risk factors of poor prognosis. Materials and methods Sixty patients who were treated by UDCA more than 1 year in our clinic were enrolled in. According to the response to UDCA by the Paris criteria, they were divided into refractory group (23 patients) and typical group (37 patients). To analyze the basic clinical conditions, biochemical markers, antibodies, liver biopsies and to detect their recent peripheral lymphocytic subsets and cytokines. Results①Compared with the typical patients, symptoms such as fatigue, pruritus and jaundice were likely to more frequent and severe in the refractory ones.②The serum levels of biochemical markers (ALT,AST,ALP,GGT,TBIL,DBIL,IgM) were much higher in refractory patients.③There were no differences between two groups in age, sex, antibodies (ANA,AMA,AMA-M2,anti-GP210,anti-SP 100 and ACA), MRS and liver biopsies.④Now, after more than one-year-UDCA-treatment, the two groups maybe share the same profile in the distribution of peripheral lymphocytic subsets; meanwhile, both of the two groups had higher percentage of B cells, CD4+T cells, CD4+ CD28+T cells and CD8+ CD28-T cells respectively than healthy controls.⑤One-year-UDCA-treatment later, the serum level of IL-6 and HGF were higher in refractory patients than typical ones. Conclusions In PBC patients, the degree of some clinical manifestations (fatigue, pruritus and jaundice) and biochemical markers levels (ALT, AST, ALP, GGT, TBIL, DBIL and IgM) probably predict the response to UDCA and progression of the disease. During the plateau phase after at least one-year treatment, refractory PBC patients tend to have higher IL-6 and HGF serum level, which suggests that the refractory PBC patients may have more severe immunologic derangement in vivo.Part Two Allogeneic bone marrow mesenchymal stem cell transplantation in refractory primary biliary cirrhosisObject To evaluate the safety and effects of allogeneic bone marrow mesenchymal stem cell transplantation in refractory primary biliary cirrhosis. Materialsand methods From the 23 PBC patients in refractory group,10 had suitable donors to accept bone marrow mesenchymal stem cell transplantation, other 13 were enrolled in blank-control-team. Simultaneously, all the patients were allowed to continue their previous UDCA or UDCA+PDL or UDCA+ AZA treatment. To compare the efficacy of UDCA with and without BM-MSC transplantation in refractory primary biliary cirrhosis throughout the follow-up. Results①No transplantation-related side effect was detected.②Pruritus, social function and emotion in PBC-40 were released by BM-MSC transplantation.③Biochemical markers such as AST, TBIL and DBIL in refractory PBC patients were cut down by BM-MSC transplantation.④BM-MSC transplantation decreased the percentage of CD8+T cells and raised that of CD4+CD25+Foxp3+T in peripheral lymphocytic subsets; it also elevated the serum level of IL-10.⑤BM-MSC transplantation seems to have no effect in improving or aggravating liver histological changes. Conclusions Allogeneic BM-MSC transplantation in refractrory PBC is safe and effective. It can ameliorate the patients'life quality and biochemical markers. The important immunoregulation role of immigrated BM-MSC in PBC probably attribute to the upgrade of CD4+CD25+ Foxp3+ T cells and IL-10 and downgrade of CD8+T Cells. Nonetheless, it seems to have little effect on liver histological progression.Part Three Characters of bone marrow mesenchymal stem cells of primary biliary cirrhosisObject To investigate the function of BM-MSC in PBC. Materials and methods To compare the growth patterns and cytokines secretions between PBC patients and healthy donors. Results①There was no difference in growth profile and speed between PBC patients and healthy donors.②Besides TGF-β1, there were no differences in excreting cytokines of two groups.③There were seldom discrepancies in cytokines concentration of culture supernatant in different generations of BM-MSC from healthy donors Conclusions BM-MSC from PBC patients may have the same characters in growth pattern and cytokines secretion as those from healthy donors.