| Part1Clinical Study on Liver Transplantation for Autoimmune HepatitisBackground&Aims:Autoimmune hepatitis (AIH) is a relatively rare indication for liver transplantation (LT) that predominantly affects females. Despite the use of immunosuppressive drugs after LT, AIH can recur and some may progress to graft failure. It is important to identify risk factors of AIH recurrence and explore new therapeutic strategies. The purpose of this study is to analyze the long-term outcomes after LT for AIH and to present our experience, including both the impact of pregnancy on AIH recurrence and the effect of simultaneous splenectomy on preventing AIH recurrence.Methods:The clinical courses of12liver transplanted patients for autoimmune hepatitis were analyzed retrospectively. All patients were women; All patients were transplanted for end-stage liver disease (ESLD) caused by chronic AIH. All patients were known to receive an immunosuppressive treatment based on corticosteroids before LT. Simultaneous splenectomy was performed in patients who received a long-term immunosuppressive treatment before LT (>1year). Patients who received a short period of immunosuppressive treatment (<1year) underwent liver transplantation with no simultaneous splenectomy.Results:The12patients were followed up for a mean of49.4months (range6to117). After a long-term immunosuppressive treatment before LT (>1year),10patients (cases1-10) underwent a simultaneous splenectomy. Two patients (cases11and12) received a short period of immunosuppressive treatment (<1year) and liver transplantation with no simultaneous splenectomy. Case1developed superior mesenteric venous thrombosis19days after LT and was cured with anticoagulation and thrombolysis. Case7developed pulmonary infection6months after LT and died of respiratory failure. Auto-antibodies disappeared slowly in3patients, however, persisted at a lower titer than before operation and were of the same type before and after LT in the rest9patients. Case11who underwent LT with no simultaneous plenectomy had relapse of AIH26months after transplantation and eventually died of graft failure99months after transplantation. No AIH recurrence was observed in patients who underwent simultaneous splenectomy. Patient1had a pregnancy9years after transplantation. The titer of autoantibody kept stable during pregnancy, slightly increased in the postpartum period and subsequently decreased to a normal level with increased prednisone doses.Conclusions:LT for AIH is usually successful with excellent long-term outcomes, but primary disease may recur due to the immunologic disturbances which are not corrected by LT. Long-term steroid therapy was needed to prevent primary disease recurrence. The concerns related to AIH recurrence after LT should be particularly considered in order to reduce the frequency of AIH recurrence and improve long-term outcomes after LT. Pregnancy may be a risk factor of AIH recurrence, and pregnancy post-liver transplantation for AIH can have a successful outcome with appropriate management. Splenectomy might be a considerable option to prevent AIH recurrence in some patients with high-risk factors. Part2Monocytes regulated by Tim-3influence hepatitis and liver cancer related to HBVBackground&Aims:Hepatocellular carcinoma (HCC) is the fifth most common cancer and third leading cause of death from cancer worldwide, and hepatocarcinogenesis is a multistep process that progresses from chronic hepatitis through cirrhosis to HCC, which is influenced by many factors. More than ninety percent of patients develop in chronic inflamed liver with HBV or HCV infection. Despite intensive surveillance programs and considerable treatment progresses, prognosis and life expectancy remain poor in HCC patients. Therefore, it is significant to explore the pathogenesis of HCC and find new therapeutic targets.In the recent years, with the development of oncomolecularbiology, more knowledge of the relationship between inflammation and tumor has been paid close attention. Many studies indicated inflammation played an important role in the tumorigenesis and progression. As we all know, macrophages, as a necessary member of innate immune, are the first line of defense in the body fight against infection and participate in a variety of inflammation-related diseases. Macrophages are plastic, and they can mainly polarize into two types according to different microenvironment and monocyte phenotype:classically activated macrophages(M1) with anti-infection and anti-tumor effects and alternatively activated macrophages(M2) with damage repair and reconstruction, the role of promoting angiogenesis and tumor growth. M1and M2are mixed in tumor tissues. M2macrophages into advantage promote tumor development.Tim-3(T cell immunoglobulin domain and mucin domain-containing molecule-3) is a newly discovered immunomodulatory molecule, regarded as a negative regulator of adaptive immunity, and related with persistent HBV infection. But the role of Tim-3in innate immune mechanism is still controversial. Whether Tim-3expression on innate immune cells from CHB to HCC is related with HCC development remains obscure. In this study, Tim-3expressions of healthy controls, CHB and HCC patients circulating monocytes were evaluated. We analyzed correlation between Tim-3 expressions and HBV/HCC-associated clinical factors and aimed to explore the effect of Tim-3on macrophage polarization and on the development of HCC, and to provide new ideas for building effective antitumor immune treatment and predicting prognosis. Methods:Tim-3expression on circulating monocytes from healthy donors, CHB and HCC patients was detected by flow cytometry. Tim-3mRNA level of PBMCs were analyzed pre-operation and post-operation in HCC patients by RT-PCR. Co-expression of CD163and Tim-3on monocytes in HCC patients was detected by flow cytometry. We use statistical methods to analyze trend of Tim-3expression on peripheral blood monocytes from healthy donors、CHB patients and HCC patients, Tim-3mRNA level change pre-operation and post-operation in HCC patients, CD163level change between Tim-3+monocytes and Tim-3" monocytes in HCC patients and correlation between Tim-3expression and HBV load、HBeAg、HBsAg、ALT level、 AST level and histopathological staging of liver cancer.Results:1. Compared with healthy controls, patients with chronic HBV infection,including CHB and HCC showed significantly elevated Tim-3expression on circulating monocytes. Tim-3expression from patients with HCC was much more than that from patients with CHB.2. Tim-3mRNA level of PBMCs and Tim-3expression on monocytes in HCC patients significantly decreased after resection of tumor.3. Tim-3expression on monocytes had no difference between HBeAg(+) and HBeAg(-) patients of CHB or HCC. Tim-3expression on monocytes had no relationship with viral load in CHB patients. These suggested Tim-3expression was not associated with HBV replication. In HCC patients, Tim-3had more expression on HBsAg(+) than HBsAg(-) patients, which indicated that Tim-3had correlation with chronic HBV infection.4. There was a strong correlation between numbers of CD14+Tim-3+cells and ALT or AST levels in CHB patients, which indicated increased Tim-3expression resulted from immune injury to liver. There was no correlation between numbers of CD14+Tim-3+cells and ALT or AST levels in HCC patients, which indicated hepatic inflammation had been inhibited.5. The numbers of CD14+Tim-3+cells has correlation with histological grade of HCC in HCC patients, which indicates Tim-3expression shows positive correlation with tumor development.6. CD163is a maker of M2phenotype phagocyte. Tim-3+monocytes has more CD163expression than Tim-3-monocytes, which indicates that Tim-3may play an important role in M2phenotype polarization.Conclusions:Tim-3expression on circulating monocytes is up-regulated from healthy controls through CHB to HCC patients and related with clinical stages of HCC, leading to M2monocyte/macrophage polarization. The microenvironment is conducive to tumorigenesis and progression of HCC. |
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