Thymalfasin (thymosin-alpha 1) therapy in patients with chronic hepatitis B

Chronic hepatitis B virus (HBV) infection is a serious clinical problem because of its world-wide distribution and potential adverse sequelae. Globally, there are approximately 350 million people infected with chronic HBV, 75% of whom live in the Asia-Pacific region. Interferon-alfa and direct anti-viral agents such as lamivudine and adefovir are effective in the therapy of chronic HBV infection but the efficacy is far from satisfactory, particularly in perinatally infected patients, patients with lower ALT levels and those with HBeAg-negative chronic hepatitis B. Thymalfasin (thymosin-alphal) is an immunoregulatory agent able to enhance Thl response. It has been shown to trigger maturational events in lymphocytes, to augment T-cell function, and to promote reconstitution of immune defects. Studies are underway in both monotherapy and combination therapy with thymalfasin and interferon and results are promising.     

Efficacy of triple therapy with thymalfasin,peginterferon α-2a,and ribavirin for the treatment of hispanic chronic HCV nonresponders: Original Article

Background/Aims: Thymalfasin has shown efficacy in the treatment of chronic HCV infection. The aim of this study was to evaluate the efficacy and tolerability of triple therapy with thymalfasin, peginterferon α-2a (PEG-IFN α-2a), and ribavirin in Hispanic patients with chronic viral hepatitis C who were nonresponders to prior treatment with interferon alfa (IFN-α)/ribavirin. Methods: In this open-label study, 40 subjects received thymalfasin (1.6 mg twice a week), PEG-IFN α-2a (180 μg once a week), and ribavirin (800-1,000 mg/ day) for 48 weeks. All patients had positive HCV RNA by PCR analysis, abnormal levels of ALT, compensated hepatic disease, and liver biopsy with chronic damage. Results: Viral response was observed in 52.5% patients at week 12 and 50% at week 24. Of the per protocol group, 52.6% showed an end-of-treatment response at week 48 and 21.1% achieved an SVR at week 72. Among genotype 1 patients, 23.5% achieved an SVR at week 72. A reduction of the dose of PEG IFN α-2a and ribavirin was required. Thymalfasin was well tolerated without dose reduction. Conclusion: Triple therapy with thymalfasin, PEG IFN α-2a, and ribavirin is an effective treatment option for difficult-to-treat HCV patients who are refractory to prior conventional treatment, with adequate tolerability.     

A randomized controlled trial of thymalfasin plus transarterial chemoembolization for unresectable hepatocellular carcinoma

Purpose  Patients with advanced hepatocellular carcinoma (HCC) have few treatment options. Thymalfasin (thymosin α-1) is an immunomodulator that may increase response to ablative therapy through direct anti-tumor action or enhanced protection against infections. We compared transarterial chemoembolization (TACE) plus thymalfasin with TACE alone for unresectable HCC. Methods  In this phase II, randomized trial, 25 patients received either TACE plus thymalfasin (1.6 mg SC, 5 times weekly; n = 14) or TACE alone (n = 11) for 24 weeks. Response was defined as transition to transplant eligibility or lack of disease progression through week 72. Survival was assessed through 24 months post-treatment. Results  Eight of fourteen (57.1%) patients in the TACE + thymalfasin group versus 5 of 11 (45.5%) patients in the TACE-only group became responders (P = 1.0). Four of fourteen TACE + thymalfasin patients versus none of 11 TACE-only patients became eligible for transplant. Median overall survival time was 110.3 weeks for the TACE + thymalfasin group versus 57.0 weeks for the TACE-only group (P = 0.45). Seven patients in each group experienced serious adverse events; there were no bacterial infections in the TACE + thymalfasin group versus 4 in the TACE-only group. There were 3 deaths in the TACE + thymalfasin group and 5 in the TACE-only group. Conclusions  In patients with unresectable HCC, TACE + thymalfasin resulted in numerically higher rates of survival and tumor response, including transplant candidacy, with fewer bacterial infections, than TACE alone. Treatment regimens for HCC including thymalfasin as an immunomodulator should be evaluated in larger trials.

Murine Coronavirus Cell Type Dependent Interaction with the Type I Interferon Response

Coronaviruses infect many species of animal including humans, causing acute and chronic diseases of many organ systems. Murine coronavirus, mouse hepatitis virus (MHV) infection of the mouse, provides animal models for the study of central nervous system disease, including encephalitis and demyelinating diseases such as Multiple Sclerosis and for hepatitis. While there are many studies of the adaptive immune response to MHV, there has until recently been scant information on the type I interferon (IFN) response to MHV. The relationship between MHV and the IFN-α/β response is paradoxical. While the type I IFN response is a crucial aspect of host defense against MHV in its natural host, there is little if any induction of IFN following infection of mouse fibroblast cell lines in vitro. Furthermore, MHV is relatively resistant to the antiviral effects of IFN-α/β in mouse fibroblast cell lines and in human 293T cells. MHV can, under some circumstances, compromise the antiviral effects of IFN signaling. The nucleocapsid protein as well as the nsp1 and nsp3 proteins of MHV has been reported to have IFN antagonist activity. However, in primary cell types such as plasmacytoid dendritic cells (pDC) and macrophages, IFN is induced by MHV infection and an antiviral state is established. Other primary cell types such as neurons, astrocytes and hepatocytes fail to produce IFN following infection and, in vivo, likely depend on IFN produced by pDCs and macrophages for protection from MHV. Thus MHV induction of IFN-α/β and the ability to induce an antiviral state in response to interferon is extremely cell type dependent. IFN induced protection from MHV pathogenesis likely requires the orchestrated activities of several cell types, however, the cell types involved in limiting MHV replication may be different in the liver and in the immune privileged CNS.     

Recurrence of Hepatocellular Carcinoma With Epithelial–Mesenchymal Transition After Spontaneous Regression: A Case Report

Hepatocellular carcinoma (HCC) is one of the most malignant cancers and ranks as the third leading cause of cancer-related death in the world. However, some patients with untreated HCC can experience spontaneous regression, a rare phenomenon that has been observed in various malignancies.Here, we report a unique case with untreated HCC, who first underwent a spontaneous cancer regression after the spontaneous clearing of chronic hepatitis B virus (HBV) infection from the liver as evidenced by hepatitis B virus surface antigen (HBsAg) seroconversion; then developed the recurrent HCC with epithelial-mesenchymal transition (EMT) after 14 years.We hypothesized that a strengthened immune system in response to HBV infection may have led to immune-mediated spontaneous cancer regression. The later recurrence of HCC may suggest the host''s immune system was no longer able to contain HCC since aging and other chronic diseases may have significantly weakened the immune surveillance.     

Immune suppression in chronic hepatitis B infection associated liver disease: A review

Hepatitis B virus(HBV) infection is one the leading risk factors for chronic hepatitis, liver fibrosis, cirrhosis and hepatocellular cancer(HCC), which are a major global health problem. A large number of clinical studies have shown that chronic HBV persistent infection causes the dysfunction of innate and adaptive immune response involving monocytes/macrophages, dendritic cells, natural killer(NK) cells, T cells. Among these immune cells, cell subsets with suppressive features have been recognized such as myeloid derived suppressive cells(MDSC),NK-reg, T-reg, which represent a critical regulatory system during liver fibrogenesis or tumourigenesis. However, the mechanisms that link HBVinduced immune dysfunction and HBV-related liver diseases are not understood.In this review we summarize the recent studies on innate and adaptive immune cell dysfunction in chronic HBV infection, liver fibrosis, cirrhosis, and HCC, and further discuss the potential mechanism of HBV-induced immunosuppressive cascade in HBV infection and consequences. It is hoped that this article will help ongoing research about the pathogenesis of HBV-related hepatic fibrosis and HBV-related HCC.     

中性粒细胞胞外诱捕网的形成机制及在肝病中的作用

中性粒细胞胞外诱捕网(NETs)是近年来新发现的中性粒细胞杀灭病原体的一种新的免疫机制。NETs的主要成分是DNA,上面附着大小不一的颗粒蛋白。NETs在肝缺血再灌注损伤、慢性乙型肝炎、肝硬化和肝癌等肝病中扮演着不同的角色。阐述了NETs的形成机制、结构组成和其在肝病中作用的研究进展。     

Emerging roles of myeloid derived suppressor cells in hepatic inflammation and fibrosis

Myeloid derived suppressor cells(MDSC) are a heterogeneous population of immune cells that are potent suppressors of immune responses. MDSC emerge in various compartments in the body, such as blood, bonemarrow or spleen, especially in conditions of cancer, infections or inflammation. MDSC usually express CD11 b, CD33, and low levels of human leukocyte antigen-DR in humans or CD11 b and Gr1(Ly6C/G) in mice, and they can be further divided into granulocytic or monocytic MDSC. The liver is an important organ for MDSC induction and accumulation in hepatic as well as extrahepatic diseases. Different hepatic cells, especially hepatic stellate cells, as well as liver-derived soluble factors, including hepatocyte growth factor and acute phase proteins(SAA, KC), can promote the differentiation of MDSC from myeloid cells. Importantly, hepatic myeloid cells like neutrophils, monocytes and macrophages fulfill essential roles in acute and chronic liver diseases. Recent data from patients with liver diseases and animal models linked MDSC to the pathogenesis of hepatic inflammation, fibrosis and hepatocellular carcinoma(HCC). In settings of acute hepatitis, MDSC can limit immunogenic T cell responses and subsequent tissue injury. In patients with chronic hepatitis C, MDSC increase and may favor viral persistence. Animal models of chronic liver injury, however, have not yet conclusively clarified the involvement of MDSC for hepatic fibrosis. In human HCC and mouse models of liver cancer, MDSC are induced in the tumor environment and suppress anti-tumoral immune responses. Thus, the liver is a primary site of MDSC in vivo, and modulating MDSC functionality might represent a promising novel therapeutic target for liver diseases.     

调节性T细胞在乙型、丙型、戊型肝炎中的作用

调节性T细胞是T淋巴细胞中一群具有主动免疫抑制作用的特殊亚群,可抑制免疫效应过度活化、维持机体免疫稳态.调节性T细胞数量的变化与自身免疫疾病、感染性疾病、肿瘤疾病和移植排斥反应的发生密切相关.本文对近年国内外关于调节性T细胞在病毒性肝炎(乙型肝炎、丙型肝炎、戊型肝炎)中作用的相关研究进行综述.     

Chronic active hepatitis in transgenic mice expressing interferon-gamma in the liver.

Interferon-gamma may play an important role in the immune response and in inflammatory diseases, including chronic active hepatitis. To understand the role of interferon-gamma in the regulation of inflammation and to establish a mouse model of chronic active hepatitis, we produced transgenic mice in which the mouse interferon-gamma gene was regulated by a liver-specific promoter, the serum amyloid P component gene promoter. Four transgenic mouse lines were generated, and two of these lines expressed mRNA of interferon-gamma in the liver. Levels of serum transaminases increased gradually as a function of age and were significantly higher than those of interferon-gamma-negative littermates after 4 weeks after birth. One transgenic mouse line showed a histology of chronic active hepatitis similar to that found in human patients, although cirrhotic changes such as fibrosis were scarce. Thus, the liver-specific production of interferon-gamma is sufficient to induce chronic inflammatory disease and this mouse is a transgenic model of chronic active hepatitis.     

骨桥蛋白在肝脏疾病中的作用机制和意义

近20余年来,有关骨桥蛋白(OPN)的生物特性及作用等研究发展迅速。OPN由多种组织细胞合成与分泌。该蛋白结构上与多种基质蛋白相似,功能上具有细胞因子的特点,它在体内参与多种生理和病理活动,包括炎症、损伤修复、骨骼形成和重建,以及癌症和肝脏疾病等。综述了目前有关骨桥蛋白的生物特性研究,及其在肝炎、肝纤维化、肝脏恶性肿瘤中发挥作用等机制。这些资料不仅揭示了相关疾病条件下,OPN在上述疾病发生、发展中所扮演的关键角色,而且指出了通过检测OPN或阻断OPN表达可以保护和治疗肝炎、肝纤维化、肝脏恶性肿瘤这一潜在的临床意义。     

Sleep,immunity and inflammation in gastrointestinal disorders

Sleep disorders have become a global issue,and discovering their causes and consequences are the focus of many research endeavors.An estimated 70 million Americans suffer from some form of sleep disorder.Certain sleep disorders have been shown to cause neurocognitive impairment such as decreased cognitive ability,slower response times and performance detriments.Recent research suggests that individuals with sleep abnormalities are also at greater risk of serious adverse health,economic consequences,and most importantly increased all-cause mortality.Several research studies support the associations among sleep,immune function and inflammation.Here,we review the current research linking sleep,immune function,and gastrointestinal diseases and discuss the interdependent relationship between sleep and these gastrointestinal disorders.Different physiologic processes including immune system and inflammatory cytokines help regulate the sleep.The inflammatory cytokines such as tumor necrosis factor,interleukin-1(IL-1),and IL-6 have been shown to be a significant contributor of sleep disturbances.On the other hand,sleep disturbances such as sleep deprivation have been shown to up regulate these inflammatory cytokines.Alterations in these cytokine levels have been demonstrated in certain gastrointestinal diseases such as inflammatory bowel disease,gastro-esophageal reflux,liver disorders and colorectal cancer.In turn,abnormal sleep brought on by these diseases is shown to contribute to the severity of these same gastrointestinal diseases.Knowledge of these relationships will allow gastroenterologists a great opportunity to enhance the care of their patients.     

Diffuse endocrine system, neuroendocrine tumors and immunity: what's new?

During the last two decades, research into the modulation of immunity by the neuroendocrine system has flourished, unravelling significant effects of several neuropeptides, including somatostatin (SRIH), and especially cortistatin (CST), on immune cells. Scientists have learnt that the diffuse neuroendocrine system can regulate the immune system at all its levels: innate immunity, adaptive immunity, and maintenance of immune tolerance. Compelling studies with animal models have demonstrated that some neuropeptides may be effective in treating inflammatory disorders, such as sepsis, and T helper 1-driven autoimmune diseases, like Crohn's disease and rheumatoid arthritis. Here, the latest findings concerning the neuroendocrine control of the immune system are discussed, with emphasis on SRIH and CST. The second part of the review deals with the immune response to neuroendocrine tumors (NETs). The anti-NET immune response has been described in the last years and it is still being characterized, similarly to what is happening for several other types of cancer. In parallel with investigations addressing the mechanisms by which the immune system contrasts NET growth and spreading, ground-breaking clinical trials of dendritic cell vaccination as immunotherapy for metastatic NETs have shown in principle that the immune reaction to NETs can be exploited for treatment.     

Protective links between vitamin D,inflammatory bowel disease and colon cancer

Vitamin D deficiency has been associated with a wide range of diseases and multiple forms of cancer including breast, colon, and prostate cancers. Relatively recent work has demonstrated vitamin D to be critical in immune function and therefore important in inflammatory diseases such as inflammatory bowel disease(IBD). Because vitamin D deficiency or insufficiency is increasingly prevalent around the world, with an estimated 30%-50% of children and adults at risk for vitamin D deficiency worldwide, it could have a significant impact on IBD. Epidemiologic studies suggest that low serum vitamin D levels are a risk factor for IBD and colon cancer, and vitamin D supplementation is associated with decreased colitis disease activity and/or alleviated symptoms. Patients diagnosed with IBD have a higher incidence of colorectal cancer than the general population, which supports the notion that inflammation plays a key role in cancer development and underscores the importance of understanding how vitamin D influences inflammation and its cancer-promoting effects. In addition to human epidemiological data, studies utilizing mouse models of colitis have shown that vitamin D is beneficial in preventing or ameliorating inflammation and clinical disease. The precise role of vitamin D on colitis is unknown; however, vitamin D regulates immune cell trafficking and differentiation, gut barrier function and antimicrobial peptide synthesis, all of which may be protective from IBD and colon cancer. Here we focus on effects of vitamin D on inflammation and inflammation-associated colon cancer and discuss the potential use of vitamin D for protection and treatment of IBD and colon cancer.     

Combination therapy of thymalfasin (thymosin-alpha 1) and peginterferon alfa-2a in patients with chronic hepatitis C virus infection who are non-responders to standard treatment

The worldwide spread of hepatitis C virus is enormous; chronic hepatitis C virus infection is a leading cause of liver cirrhosis and hepatocellular carcinoma. While treatment options have improved substantially over the last decade, responses are still disappointing, particularly in certain difficult-to-treat groups such as patients who are immunosuppressed or have decompensated disease. Preliminary studies have indicated that combined treatment strategies may provide effective approaches for the future. The combination of thymalfasin with pegylated interferon is currently a promising option for the treatment of patients with chronic hepatitis C virus infection. An ongoing phase 3 study in the USA should provide much needed data to improve the outcome for these patients.     

T cell immunopathogenesis and immunotherapeutic strategies for chronic hepatitis B virus infection

Hepatitis B is caused by the host immune response and T cells play a major role in the immunopathogenesis. More importantly, T cells not only destroy hepatocytes infected by hepatitis B virus (HBV), but also control HBV replication or eradicate HBV in a noncytolytic manner. Therefore, analysis of T cell immune response during acute and chronic HBV infection is important to develop a strategy for successful viral control, which could lead to immunotherapy for terminating persistent HBV infection. There have been many attempts at immunotherapy for chronic HBV infection, and some have shown promising results. High viral load has been shown to suppress antiviral immune responses and immunoinhibitory signals have been recently elucidated, therefore, viral suppression by nucleos(t)ide analogs, stimulation of antiviral immune response, and suppression of the immunoinhibitory signals must be combined to achieve desirable antiviral effects.     

Nueva inmunoterapia y cáncer de pulmón

Recent research on the relationship between the immune system and cancer has revealed the molecular mechanisms by which cancer cells co-opt certain T cell receptors which block the cytotoxic response to defend themselves from the antitumor immune attack. These findings have helped identify specific targets (T cell receptors or their corresponding ligands) for the design of monoclonal antibodies that can unlock the immune response.These drugs, known as immune checkpoint inhibitors, have shown efficacy in metastatic melanoma and kidney cancer, and have been successfully tested in non-small cell lung cancer in recent trials. Immune checkpoint inhibitors were included in clinical practice as a second-line option after an initial chemotherapy (CT) regimen, and in the last year positive results have been reported from randomized trials in which they were compared in first line with standard CT. Responses have been surprising and durable, but less than 20%-25% in unselected patients, so it is essential that factors predicting efficacy be identified. One such biomarker is PD-L1, but the different methods used to detect it have produced mixed results.This non-systematic review discusses the results of the latest trials, the possibilities of incorporating these drugs in first-line regimens, the criteria for patient selection, adverse effects, and the prospects of combinations with conventional treatment modalities, such as CT, radiation therapy, and antiangiogenic agents.     

Prevention of hepatocellular carcinoma: Focusing on antioxidant therapy

Oxidative stress has been investigated in the context of alcoholic liver injury for many years and shown to be a causal factor of chronic hepatitis C (CHC), nonalcoholic steatohepatitis (NASH), drug-induced liver injury, Wilson’s disease, and hemochromatosis. In CHC, it has been demonstrated that oxidative stress plays an important role in hepatocarcinogenesis. In cases with persistent hepatitis due to failure of hepatitis C virus eradication, or chronic liver disease, such as NASH, the treatment of which remains unestablished, it is important to reduce serum alanine aminotransferase levels and prevent liver fibrosis and development of hepatocellular carcinoma. This also suggests the importance of antioxidant therapy. Among treatment options where it would be expected that anti-inflammatory activity plays a role in their confirmed efficacy for chronic hepatitis, iron depletion therapy, glycyrrhizin, ursodeoxycholic acid, Sho-Saiko-To, and vitamin E can all be considered antioxidant therapies. To date, however, the ability of these treatments to prevent cancer has been confirmed only in CHC. Nevertheless, anti-inflammatory and anti-fibrotic effects have been demonstrated in other liver diseases and these therapies may potentially be effective for cancer prevention.