The liver has unique immune regulatory functions that promote the induction of tolerance rather than responses to antigens encountered locally. These functions are mediated by local expression of ...coinhibitory receptors and immunosuppressive mediators that help prevent overwhelming tissue damage. Over the years, we have gained more insight into the local regulatory cues that determine the functional complexity of immune responses regulated locally in the liver. Both the unique hepatic microenvironment and the particular liver sinusoidal cell populations, in addition to hepatocytes, actively modulate immune responses locally in the liver and thereby determine the outcome of hepatic immune responses. This is of high biological and clinical relevance in hepatitis B virus and hepatitis C virus infections, which can cause acute and persistent infections associated with chronic inflammation in humans that eventually progress to cirrhosis and hepatocellular carcinoma. Here, we review current knowledge about the balance between immunity and tolerance in the liver and how this may affect our understanding of the determinants of hepatitis B virus and hepatitis C virus clearance, persistence, and virus-induced liver disease.
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with limited therapeutic options. Since HCC has been shown to be immunogenic, T cell-based immunotherapy is considered ...a promising treatment. In this review, we summarize current knowledge of T cell responses against tumour-associated antigens, as well as the mechanisms underlying the poor quality of these responses in patients with HCC. Insights into these important aspects of HCC immunology are crucial for the further development of novel immunotherapies.
There is consensus that HCV-specific T cells play a central role in the outcome (clearance vs. persistence) of acute infection and that they contribute to protection against the establishment of ...persistence after reinfection. However, these T cells often fail and the virus can persist, largely as a result of T cell exhaustion and the emergence of viral escape mutations. Importantly, HCV cure by direct-acting antivirals does not lead to a complete reversion of T cell exhaustion and thus HCV reinfections can occur. The current lack of detailed knowledge about the immunological determinants of viral clearance, persistence and protective immunity is a major roadblock to the development of a prophylactic T cell vaccine. This minireview highlights the basic concepts of successful T cell immunity, major mechanisms of T cell failure and how our understanding of these concepts can be translated into a prophylactic vaccine.
Abstract
Effective innate and adaptive immune responses are essential for the control of hepatitis C virus (HCV) infection. Indeed, elimination of HCV during acute infection correlates with an early ...induction of innate and a delayed induction of adaptive immune responses. However, in the majority of acutely HCV-infected individuals, these responses are insufficient to clear the virus and persistence develops. In recent years, different mechanisms responsible for the failure of innate and adaptive immune responses have been identified. These include the proteolytic cleavage of molecules playing key roles in the induction of the interferon response, manipulation of interferon-induced effector proteins, interference with CD8+ T-cell function or immune escape in T- and B-cell epitopes. In this review, we discuss the possible roles of innate and adaptive immune responses in HCV clearance and the different evasion strategies used by the virus to escape these immune responses.
Hepatitis C virus utilizes several different mechanisms to evade innate and adaptive immune responses and has thus a unique opportunity to establish viral persistence in the majority of acutely infected patients.
Abstract
The origin of SARS-CoV-2 variants of concern remains unclear. Here, we test whether intra-host virus evolution during persistent infections could be a contributing factor by characterizing ...the long-term SARS-CoV-2 infection dynamics in an immunosuppressed kidney transplant recipient. Applying RT-qPCR and next-generation sequencing (NGS) of sequential respiratory specimens, we identify several mutations in the viral genome late in infection. We demonstrate that a late viral isolate exhibiting genome mutations similar to those found in variants of concern first identified in UK, South Africa, and Brazil, can escape neutralization by COVID-19 antisera. Moreover, infection of susceptible mice with this patient’s escape variant elicits protective immunity against re-infection with either the parental virus and the escape variant, as well as high neutralization titers against the alpha and beta SARS-CoV-2 variants, B.1.1.7 and B.1.351, demonstrating a considerable immune control against such variants of concern. Upon lowering immunosuppressive treatment, the patient generated spike-specific neutralizing antibodies and resolved the infection. Our results suggest that immunocompromised patients could be a source for the emergence of potentially harmful SARS-CoV-2 variants.
Differentiation and fate of virus-specific CD8
T cells after cessation of chronic antigen stimulation is unclear. Here we show that a TCF1
CD127
PD1
hepatitis C virus (HCV)-specific CD8
T-cell subset ...exists in chronically infected patients with phenotypic features of T-cell exhaustion and memory, both before and after treatment with direct acting antiviral (DAA) agents. This subset is maintained during, and for a long duration after, HCV elimination. After antigen re-challenge the less differentiated TCF1
CD127
PD1
population expands, which is accompanied by emergence of terminally exhausted TCF1-CD127-PD1
HCV-specific CD8
T cells. These results suggest the TCF1
CD127
PD1
HCV-specific CD8
T-cell subset has memory-like characteristics, including antigen-independent survival and recall proliferation. We thus provide evidence for the establishment of memory-like virus-specific CD8
T cells in a clinically relevant setting of chronic viral infection and we uncover their fate after cessation of chronic antigen stimulation, implicating a potential strategy for antiviral immunotherapy.
Adaptive Immune Response against Hepatitis C Virus Kemming, Janine; Thimme, Robert; Neumann-Haefelin, Christoph
International journal of molecular sciences,
08/2020, Letnik:
21, Številka:
16
Journal Article
Recenzirano
Odprti dostop
A functional adaptive immune response is the major determinant for clearance of hepatitis C virus (HCV) infection. However, in the majority of patients, this response fails and persistent infection ...evolves. Here, we dissect the HCV-specific key players of adaptive immunity, namely B cells and T cells, and describe factors that affect infection outcome. Once chronic infection is established, continuous exposure to HCV antigens affects functionality, phenotype, transcriptional program, metabolism, and the epigenetics of the adaptive immune cells. In addition, viral escape mutations contribute to the failure of adaptive antiviral immunity. Direct-acting antivirals (DAA) can mediate HCV clearance in almost all patients with chronic HCV infection, however, defects in adaptive immune cell populations remain, only limited functional memory is obtained and reinfection of cured individuals is possible. Thus, to avoid potential reinfection and achieve global elimination of HCV infections, a prophylactic vaccine is needed. Recent vaccine trials could induce HCV-specific immunity but failed to protect from persistent infection. Thus, lessons from natural protection from persistent infection, DAA-mediated cure, and non-protective vaccination trials might lead the way to successful vaccination strategies in the future.
Current international guidelines recommend endoscopic resection for T1 colorectal cancer (CRC) with low-risk histology features and oncologic resection for those at high risk of lymphatic metastasis. ...Exact risk stratification is therefore crucial to avoid under-treatment as well as over-treatment. Endoscopic full-thickness resection (EFTR) has shown to be effective for treatment of non-lifting benign lesions. In this multicenter, retrospective study we aimed to evaluate efficacy, safety, and clinical value of EFTR for early CRC.
Records of 1234 patients undergoing EFTR for various indications at 96 centers were screened for eligibility. A total of 156 patients with histologic evidence of adenocarcinoma were identified. This cohort included 64 cases undergoing EFTR after incomplete resection of a malignant polyp (group 1) and 92 non-lifting lesions (group 2). Endpoints of the study were: technical success, R0-resection, adverse events, and successful discrimination of high-risk versus low-risk tumors.
Technical success was achieved in 144 out of 156 (92.3%). Mean procedural time was 42 minutes. R0 resection was achieved in 112 of 156 (71.8%). Subgroup analysis showed a R0 resection rate of 87.5% in Group 1 and 60.9% in Group 2 (P < .001). Severe procedure-related adverse events were recorded in 3.9% of patients. Discrimination between high-risk versus low-risk tumor was successful in 155 of 156 cases (99.3%). In Group 1, 84.1% were identified as low-risk lesions, whereas 16.3% in group 2 had low-risk features. In total, 53 patients (34%) underwent oncologic resection due to high-risk features whereas 98 patients (62%) were followed endoscopically.
In early colorectal cancer, EFTR is technically feasible and safe. It allows exact histological risk stratification and can avoid surgery for low-risk lesions. Prospective studies are required to further define indications for EFTR in malignant colorectal lesions and to evaluate long-term outcome.
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The hepatitis B (HB) vaccine is effective for the prevention of HB virus infection. It has been widely accepted that an anti‐HB surface antibody (HBs) level ≥10 mIU/mL is protective against HB virus ...infection. Although transient infection can occur in individuals who attain a peak level of anti‐HBs ≥10 mIU/mL after primary vaccination, long‐term follow‐up studies show that successful primary vaccination can prevent individuals from acute clinical hepatitis and chronic infection. Healthcare workers (HCWs) are at‐risk individuals. Based on the accumulated data, the USA considers an anti‐HBs level ≥10 mIU/mL to constitute successful vaccination for HCWs. In contrast, because some anti‐HBs assays cannot accurately measure in the low anti‐HBs range, including 10 mIU/mL, the UK and Germany consider an anti‐HBs level ≥100 mIU/mL to constitute successful vaccination for HCWs. In the USA and UK, a booster dose is unnecessary for HCWs after successful vaccination. In Germany, anti‐HBs testing is recommended for HCWs who are at particularly high individual exposure risk 10 years after successful primary immunization, and a booster dose is offered if the anti‐HBs level has declined to ˂100 mIU/mL. The differences in the goal of HB vaccination, reliability of anti‐HBs assays, and use of booster vaccination cause discordance in HB vaccination policies for HCWs.
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