Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019158 (hepatitis)
 30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human telomerase reverse transcriptase, hTERT, has been identified as the catalytic enzyme required for telomere elongation. hTERT is expressed in most tumor cells but seldom expressed in most human adult cells. It has been reported that 80% to 90% of hepatocellular carcinomas (HCCs) express hTERT, making the enzyme a potential target in immunotherapy for HCC. In the current study, we identified hTERT-derived, HLA-A*2402-restricted cytotoxic T cell (CTL) epitopes and analyzed hTERT-specific CTL responses in patients with HCC. Peptides containing the epitopes showed high affinity to bind HLA-A*2402 in a major histocompatibility complex binding assay and were able to induce hTERT-specific CTLs in both hTERT cDNA-immunized HLA-A*2402/Kb transgenic mice and patients with HCC. The CTLs were able to kill hepatoma cell lines depending on hTERT expression levels in an HLA-A*2402-restricted manner and induced irrespective of hepatitis viral infection. The number of single hTERT epitope-specific T cells detected by ELISPOT assay was 10 to 100 specific cells per 3 x 10(5) PBMCs, and positive T cell responses were observed in 6.9% to 12.5% of HCC patients. hTERT-specific T cell responses were observed even in the patients with early stages of HCC. The frequency of hTERT/tetramer+ CD8+ T cells in the tumor tissue of patients with HCC was quite high, and they were functional. In conclusion, these results suggest that hTERT is an attractive target for T-cell-based immunotherapy for HCC, and the identified hTERT epitopes may be valuable both for immunotherapy and for analyzing host immune responses to HCC.
 ...
PMID:Cytotoxic T cell responses to human telomerase reverse transcriptase in patients with hepatocellular carcinoma. 1672 33

Presentation of class I major histocompatibility complex (MHC) is severely down-regulated on hepatocytes in chronic hepatitis caused by woodchuck hepatitis virus (WHV). To determine which of the viral proteins mediates class I MHC antigen suppression, cultured normal woodchuck hepatocytes were transfected with the complete WHV genome, sequences encoding individual virus proteins, or whole virus genomes in which transcription of selected proteins was disabled by site-specific mutagenesis. It was found that hepatocyte presentation of class I MHC antigen was significantly inhibited following transfection with complete WHV genome or with viral subgenomic fragments encoding envelope pre-S2 protein or pre-S1 protein, which naturally encompasses pre-S2 amino acid sequence. In contrast, hepatocytes transfected with WHV X gene alone demonstrated a profound enhancement in the class I antigen display, whereas those expressing virus major S protein or nucleocapsid (core) protein were not different from control hepatocytes. Analysis of the mutated WHV sequences confirmed that the envelope pre-S2 protein was responsible for inhibition of the class I MHC antigen display. Interestingly, treatment with recombinant woodchuck gamma interferon (rwIFN-gamma) restored the inhibited presentation of the class I antigen. Moreover, the class I antigen suppression was not associated with down-regulation of hepatocyte genes for class I MHC heavy chain, beta(2)-microglobulin, transporters associated with antigen processing, and proteasome subunits. These findings indicate that the defective presentation of class I MHC antigen on hepatocytes transcribing WHV is a consequence of posttranscriptional suppression exerted by virus pre-S2 protein and that this hindrance can be fully reversed by IFN-gamma.
 ...
PMID:Inhibition by woodchuck hepatitis virus of class I major histocompatibility complex presentation on hepatocytes is mediated by virus envelope pre-S2 protein and can be reversed by treatment with gamma interferon. 1691 4

Hepatitis C virus (HCV) is known for its ability to establish persistent infection and cause chronic hepatitis in most infected individuals. The pathogenesis of hepatic injury and the precise mechanisms underlying viral persistence are unknown. Accumulating evidence indicates that successful elimination of HCV is associated with the induction and maintaining of strong helper T-cell and cytotoxic T-cell responses against multiple viral epitopes. In contrast, patients who develop chronic HCV infection are characterized by the lack of strong viral-specific helper T-cell responses. The failure to mount and maintain strong HCV-specific T-cell responses may be determined by the genetics, especially the major histocompatibility complex background, of the host. However, it is likely that other host and viral factors are also involved in determining the outcome of HCV infection. Available data suggest that HCV is not cytopathic to hepatocytes and that liver injury associated with chronic HCV infection is likely to be mediated by immune responses against HCV-infected hepatocytes. In addition to hepatitis, HCV infection may also cause breaching of immune tolerance, leading to autoimmune disorders. Although the lack of a small animal model and a tissue culture system has impeded research on hepatitis C virus (HCV) infection, recent studies in humans and chimpanzees have significantly enhanced our understanding of the interaction between HCV and the host's immune system. This review focuses on the most recent advances in our understanding of the immunology of HCV infection. In particular, the possible mechanisms of how HCV establishes chronic infection are discussed. The pathogenesis of liver injury, the immunogenetics of HCV infection, and the effect of HCV infection on host's immune function are also reviewed.
 ...
PMID:Immunology of hepatitis C virus infection. 1703 Nov 38

Genome scanning studies suggest an important role for genes outside the major histocompatibility complex in autoimmunity. Key candidates are those genes involved in immune regulation and preservation of immune homeostasis, including the genes involved in apoptosis. Our aim was to determine the association between the Fas gene polymorphism at position -670 and susceptibility, clinical expression, and outcome in type 1 autoimmune hepatitis (AIH). An adenosine to guanine single nucleotide polymorphism in the Fas gene (TNFRSF6) promoter was assessed in 149 well-characterized Caucasoid patients and 172 matched controls. Patients and normal subjects had the similar TNFRSF6-670 allele and genotype frequencies. Serum aspartate aminotransferase (510 +/- 77 vs 283 +/- 53 U/l), gamma-globulin (3.3 +/- 0.2 vs 2.6 +/- 0.2 g/dl), and immunoglobulin G (2976 +/- 223 vs 2324 +/- 203 mg/dl) levels were higher in patients with the guanine/guanine genotype than in those with the adenosine/adenosine genotype. Cirrhosis at presentation was more common in patients with the adenosine/adenosine or adenosine/guanine genotypes than in those with the guanine/guanine genotype (29% vs 6%). Polymorphism of the Fas gene at position -670 does not influence susceptibility to AIH, but may affect the early development of cirrhosis.
 ...
PMID:A functional Fas promoter polymorphism is associated with a severe phenotype in type 1 autoimmune hepatitis characterized by early development of cirrhosis. 1749 46

After the initial dramatic effects, observed in a Lewis lung carcinoma animal model, using a combination of thymosin alpha 1 (Talpha1) and interferon (IFN) after cyclophosphamide, a number of other preclinical models in mice (Friend erythroleukemia and B16 melanoma) and in rats (DHD/K12 colorectal cancer liver metastasis) have confirmed the efficacy of the combination therapy with Talpha1 and either IFN or IL-2 plus chemotherapy. These results provided the scientific foundation for the first clinical trials using Talpha1 in combination with BRMs and/or chemotherapy. Pivotal trials in advanced non-small cell lung cancer (NSCLC) and melanoma with Talpha1 and IFN-alpha low doses after cis-platinum or dacarbazine produced the first evidence of the high potentiality of this approach in the treatment of human cancer. The combination of Talpha1 and IFN-alpha was also used in patients affected by chronic B and C hepatitis including IFN-nonresponders and infected by precore mutants or genotype 1b. Further studies demonstrated additional biological activities clarifying the mechanism of action of Talpha1, partially explaining the synergism with IFN. It has been shown the capacity of activating infected dendritic cells through Toll-like receptor signaling, thus influencing the inflammation balance, and of increasing the expression of tumor, viral, and major histocompatibility complex (MHC) I antigens. Dose-response studies suggested the possibility of improving the efficacy of this molecule reducing the overall toxic. Based on these information two clinical trials are ongoing: a large phase II on advanced melanoma patients treated with Talpha1 at different doses after dacarbazine and a phase III one, on IFN-resistant hepatitis C virus (HCV) patients treated with a triple combination (IFN, ribavirin, and Talpha1).
 ...
PMID:Thymosin alpha 1: from bench to bedside. 1760 Feb 90

Autoimmune hepatitis is a polygenic disorder of unknown cause in which the genetic risk factors that affect occurrence, clinical phenotype, severity, and outcome still are being clarified. The susceptibility alleles in white North American and northern European patients reside on the DRB1 gene, and they are DRB1*0301 and DRB1*0401. These alleles encode a 6 amino acid sequence at positions 67-72 in the DRbeta polypeptide chain of the class II molecules of the major histocompatibility complex. This sequence is associated with susceptibility, and lysine at position DRbeta71 is the key determinant. Molecular mimicry between foreign and self-antigens may explain the loss of self-tolerance and the occurrence of concurrent immune diseases in anatomically distant organs. Disease severity is associated with the number of alleles encoding lysine at DRbeta71 (gene dose) and the number of polymorphisms, including those of the tumor necrosis factor-alpha gene, cytotoxic T lymphocyte antigen-4 gene, and tumor necrosis factor-receptor superfamily gene, that can modify the immune response. Individuals in different geographic regions may have different susceptibility alleles that reflect indigenous triggering antigens, and these may provide clues to the etiologic agent. Knowledge of the genetic predispositions for autoimmune hepatitis may elucidate pathogenic mechanisms, identify etiologic agents, characterize susceptible populations, foresee outcomes, and target new therapies. These lessons may be applicable to autoimmune disease in general.
 ...
PMID:Genetic factors affecting the occurrence, clinical phenotype, and outcome of autoimmune hepatitis. 1832 91

Several pharmacogenetics studies have analyzed the influence of specific genetic polymorphisms on the toxicity of antiretroviral treatment. The present review describes some of the adverse effects of antiretroviral drugs in which a genetic predisposition may be involved: efavirenz-induced neurological toxicity, generally associated with the 516G>T polymorphism of liver enzyme cytochrome P450 2B6 (CYP2B6); hypersensitivity reactions to nevirapine, associated with specific alleles of major histocompatibility complex, mainly the HLA-DRB1*0101 allele, which, in combination with a high CD4 lymphocyte count, has been associated with systemic reactions and hepatitis in Caucasians, and the HLA-Cw8 allele, which is associated with hypersensitivity reactions in persons from the Italian island of Sardinia and from Japan; nevirapine-induced hepatotoxicity associated with the C>T polymorphism in position 3435T of the ABCB1 (MDR-1) gene codifying for glycoprotein P (lower risk); hyperbilirubinemia in patients exposed to atazanavir or indinavir carrying the UGT1A1*28 polymorphism; peripheral neuropathy with nucleoside analogues associated with haplogroup T of the mitochondrial genome (higher risk) and with the HFE C282Y genotype of the hemochromatosis gene (lower risk); the mutation in codon 964 (R964C) of the POLG gene that codifies the mitochondrial polymerase DNA gamma described in a Thai patient with lactic acidosis; the ABCC2 gene haplotypes associated with tenofovir-induced proximal tubulopathy, and the risk of pancreatitis in persons with mutations in the CFTR and SPINK-1 genes.
 ...
PMID:[Toxicogenetics of antiretroviral treatment (II): neurotoxicity, hepatotoxicity, lactic acidosis, kidney damage, and other adverse effects of antiretroviral drugs]. 1868 Jun 93

Doberman hepatitis (DH) is a chronic and progressive inflammatory liver disease that mainly affects female dogs. The high incidence of chronic hepatitis in Dobermans is suggestive of a genetic predisposition. DH is characterized by mononuclear cell infiltration and copper accumulation in the liver and major histocompatibility complex (MHC) class II antigen expression in the hepatocytes. In dogs, the MHC is referred to as the dog leukocyte antigen (DLA) system. In this study, the potential role of DLA genes in DH was investigated by sequence-based typing in the exon 2 of DLA-DRB1, -DQA1 and -DQB1. The case group comprised 37 Dobermans with subclinical or clinical DH. The control group consisted of 37 healthy Dobermans, with normal liver enzyme values and without immunosuppressive medication. The control dogs were over 10 years old to include dogs with the lowest genetic risk of DH. Our results indicate that Dobermans with homozygous DLA-DRB1*00601/DQA1*00401/DQB1*01303 [odds ratio (OR) = 14.9, confidence limit (CL) = 3.1-71.7, P < 0.00005], especially with homozygosity for DLA-DRB1*00601 (P < 0.0005), are susceptible to DH. The DQ heterodimer DLA-DQA1*00901/DQB1*00101 and the allele DLA-DRB1*01501 appear to confer protection against DH (P < 0.001). Allele and haplotype frequencies were compared using chi-squared statistics. The disease shows a complex pattern of inheritance, but the observed DLA class II association with DH suggests a role for the immune system in the development of the disease.
 ...
PMID:Association of Doberman hepatitis to canine major histocompatibility complex II. 2094 86

Autoimmune hepatitis is a chronic inflammatory disease of the liver with a dismal prognosis when left untreated. Key for the improvement of prognosis is a timely diagnosis before cirrhosis has developed. This is reached by the exclusion of other causes of hepatitis, elevated immunoglobulin G, autoantibody profile and histological assessment. Treatment achieves remission rates in 80% of individuals and consists of immunosuppression with corticosteroids and azathioprine. A recent randomised controlled multicenter trial has added budesonide to the effective treatment options in non-cirrhotic patients and leads to a reduction of unwanted steroid side effects. Autoimmune hepatitis is an autoimmune disease of unknown aetiology. Association studies of major histocompatibility complex and other genes demonstrate an influence of immunogenetics. However, apart from the autoimmune polyglandular syndrome type 1, in which 10% of patients suffer from an autoantibody-positive autoimmune hepatitis linked to mutations of the autoimmune regulator gene, there is no clear evidence for a hereditary aetiology of this disease.
 ...
PMID:Autoimmune hepatitis. 2095 69

Baicalin from Scutellaria baicalensis is a major flavonoid constituent found in the traditional Chinese medicinal herb Baikal skull cap. It has been widely used for the treatment of various diseases such as pneumonia, diarrhea, and hepatitis. Recent studies have demonstrated that baicalin possesses a wide range of pharmacological and biological activities, including anti-inflammatory, anti-microbial, anti-oxidant, and anti-tumor properties. Specifically, its anti-inflammatory activity has been estimated in various animal models of acute and chronic inflammation; however, its effects on dendritic cells (DCs) maturation and immuno-stimulatory activities are still unknown. In this study, we attempted to determine whether baicalin could influence DC surface molecule expression, antigen uptake capacity, cytokine production, and capacity to induce T-cell differentiation. Baicalin was shown to significantly suppress the expression of surface molecules CD80, CD86, major histocompatibility complex (MHC) class I, and MHC class II as well as the levels of interleukin-12 production in lipopolysaccharide stimulated DCs. Moreover, baicalin-treated DCs showed an impaired induction of the T helper type 1 immune response and a normal cell-mediated immune response. These findings provide important understanding of the immunopharmacological functions of baicalin and have ramifications for the development of therapeutic adjuvants for the treatment of DCs-related acute and chronic diseases.
 ...
PMID:Baicalin from Scutellaria baicalensis impairs Th1 polarization through inhibition of dendritic cell maturation. 2341 70


<< Previous 1 2 3 4 5 6 7 8 Next >>