Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatitis C virus (HCV) readily establishes high-level lifelong persistent infection in the majority of immunocompetent adults with failure of HCV-specific CD8+ CTL to clear viral replication. Virus-induced conditioning of innate immune responses is a possible mechanism that may contribute to the impairment of virus-specific CD8+ CTL responses. Here, we analyzed whether triggering of NK cell receptor expression and function is affected during chronic viremic HCV infection. Flow cytometric analysis of purified resting peripheral NK cells showed no evidence of NK cell activation, while analysis of natural cytotoxicity receptors (NCR) showed that NK cells from HCV-infected patients had selective increased expression of NKp30 and NKp46. NK cells had corresponding conserved cytotoxic activity against all targets with the exception of HepG2 hepatoma cells. Freshly separated NK cells from HCV patients showed significant production of IL-10 and normal concentrations of IFN-gamma upon cell-mediated triggering. Thus, increased expression of NKp30 during HCV infection with increased IL-10 production could contribute, once NK cells localize in the liver, to a NK-DC crosstalk leading to skewing of subsequent adaptive immune responses and lack of virus control.
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PMID:Increased natural cytotoxicity receptor expression and relevant IL-10 production in NK cells from chronically infected viremic HCV patients. 1727 91

Tumor cells may escape from the immune responses because of defective differentiation of dendritic cells (DC). Recent studies have found an increased number of regulatory T cells (Treg) in both peripheral blood and tissues from patients with hepatocellular carcinoma. In the present study, we used tumor culture supernatants (TSN) from hepatoma-derived cell lines to investigate whether TSN interfere with the differentiation of human monocyte-derived DC and/or their ability to increase Treg. The results showed that exposure to TSN significantly inhibited the differentiation of monocytes into DC with retained CD14 molecule and reduced expression of CD1a. These TSN-exposed immature DC also produced significant amount of immunosuppressive cytokine IL-10 and displayed an increased expression of co-stimulatory molecules. Upon stimulation with LPS, however, the TSN-exposed DC failed to undergo full maturation, with a blockage of the upregulation of co-stimulatory molecules on their surface and a switch to an IL-10(high)IL-12(low)TNF-alpha(low) phenotype. Moreover, exposure of DC to TSN selectively inhibited their capacity to stimulate the proliferation of allogeneic CD8(+) T cells, but promoted the generation of CD4(+)CD25(hi)Foxp3(+) Treg cells. These findings, together with previous clinical studies showing that CD4(+)CD25(hi) Treg cells are concentrated within hepatocellular carcinoma tissue, suggest that the local tumor microenvironment may favor the induction of Treg cells through inhibiting the differentiation and maturation of DC.
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PMID:Hepatoma cells inhibit the differentiation and maturation of dendritic cells and increase the production of regulatory T cells. 1794 51

The dendritic cell (DC)-based tumor immunotherapy has been a new promise of cure for cancer patients, but animal studies and clinical trials have thus far only shown limited success, especially in treating established tumors. Certain immunosuppressive mechanisms triggered by tumor cells or the derivatives are believed to be a major obstacle. We studied the role of DC-derived IL-10 and its negative impact on vaccine efficacy in mouse models. Liver tumor cells were injected via the portal vein, giving rise to disseminated intrahepatic tumors, or s.c. to form solid but extrahepatic tumors. Bone marrow-derived DCs were generated from normal or IL-10-deficient mice and used as the vector to deliver tumor Ags. We demonstrate here that DCs devoid of IL-10, a potent immunosuppressive cytokine, are superior over conventional DCs in triggering antitumor immunity. The IL-10(-/-)DCs were highly immunogenic, expressed enhanced levels of surface MHC class II molecules, and secreted increased amounts of Th1-related cytokines. By inducing tumor-specific killing and through the establishment of immunological memory, the vaccines delivered by IL-10(-/-)DCs could evoke strong therapeutic and protective immunity against hepatocellular carcinoma in the mouse models. These findings will have great clinical impact once being translated into the treatment of malignant, and potentially infectious, diseases in humans.
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PMID:A crucial role for dendritic cell (DC) IL-10 in inhibiting successful DC-based immunotherapy: superior antitumor immunity against hepatocellular carcinoma evoked by DC devoid of IL-10. 1794 74

Hepatitis C chronic infection occurs in 80% of the cases and eventually leads to cirrhosis and hepatocellular carcinoma. A deficient adaptive immune response has been described during chronic infection which contributes to viral persistence. This altered T cell response could be associated to deficient costimulation signals during priming of T cells. We have conducted an in vitro study to explore the activation phenomenon of CD4+ T cells focusing on costimulation via the CD28 receptor, associated to stimulation with purified Hepatitis C (HCV) core antigen. Our study involved the induction of CD69, CD25 and CD40L activation receptors, along with detection of intracellular cytokines such as IFN-gamma, TGF-beta and IL-10. Analysis was performed in chronically HCV infected patients, intrafamilial members of HCV-infected patients and healthy individuals. HCV core antigen induced CD40L expression in CD4+ cells from intrafamilial members, in contrast to chronically infected patients and control individuals. Association of CD28 crosslinking increased CD69 and IFN-gamma expression in chronically infected patients, suggesting a detriment in this signaling pathway. Additionally, an increased TGF-beta expression was observed in CD4+ cells from HCV-infected patients, which was corrected by addition of CD28 crosslinking. Our results may contribute to understand the underlying mechanism of T cell tolerance against HCV during chronic infection, and to provide new targets for the designing of therapeutic strategies to control the infection and to offer protective immunity against the virus.
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PMID:[Impaired activation and costimulation of T CD4+ lymphocytes during chronic hepatitis C infection]. 1884 76

This study explores the novel H22 whole-cell vaccine of active specific immunotherapy in the treatment of hepatocellular carcinoma. H22 hepatoma tumor vaccine modified by human interleukin-2 (hIL-2) and mouse granulocyte-monocyte colony-stimulating factor (mGM-CSF) fusion gene was prepared to study its specific anti-tumor immunity. Mice were inoculated by these vaccines. Then tumor cells were injected into mouse models. The (51)Cr release assay was used to examine the cytotoxicities of the splenocytes to H22 hepatoma cells in immunized mice, tumor-bearing mice and control mice. The blood was needed to test the level of IL-10 and interferon (IFN)-gamma in serum. Survival time of mice was calculated. Specific cytotoxicity rate of splenocytes from the immunized mice to H22 cancer cell was 38%, significantly higher than 13.6% in the tumor-bearing group, 7.5% in the control group, and 9.1% in S180 cells (p<0.05). Serum IFN-gamma in the immunized group was significantly increased compared with other groups (p<0.01), and serum IL-10 in the immunized group was significantly decreased compared with other groups (p<0.01). The survival time of the transgenic vaccinated group was significantly longer.
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PMID:Experimental study of specific immunotherapy induced by H22 autologous tumor as whole tumor cell vaccine. 1884 36

Increasing evidence indicates the immunosuppressive nature of the local environment in tumor. The present study was focused on analyzing the immune status within hepatocellular carcinoma. In contrast to the increasing number of CD4(+) T cells, CD8(+), CD3(-)CD56(+), CD3(+)CD56(+), and gammadeltaT cells were all found to be under-represented in tumor infiltrating lymphocytes. Notably, the relative abundance of CD3(+)CD56(+) cells appeared to be correlated with patient survival. Functional analysis demonstrated that CD4(+) cells in the tumor tended to produce more IL-10 but less IFN-gamma, whereas CD8(+) cells showed impaired capacity for the production of both IFN-gamma and perforin. Consistent with previous reports, we observed a significant increase of Foxp3(+) cells in the tumor tissue. Intriguingly, although over 90% of CD4(+)CD25(high) cells were found to be Foxp3(+), the majority of Foxp3(+) cells were identified in the CD4(+)CD25(medium) and CD4(+)CD25(-) subsets. In support of its role as a negative regulator, CD4(+)CD25(high) cells suppressed the proliferation of CD4(+)CD25(-) cells isolated from the same tissues in an APC dependent manner. In conclusion, the tumor microenvironment of hepatocellular carcinoma is featured by the presence of multiple immunosuppressive factors.
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PMID:The immunosuppressive tumor microenvironment in hepatocellular carcinoma. 1894 44

The recently identified decoy receptor 3 (DcR3) inhibits FasL-induced apoptosis by binding to FasL, and it is considered to play a key role in the immune escape system of neoplastic cells. In order to examine the involvement of DcR3 in the immunologic tolerance of hepatocellular carcinoma (HCC), we investigated the amplification and expression of DcR3, FasL, and Fas in an HCC mice model using RT-PCR, western blotting, and ELISA, and analyzed the space-time relationship with various cytokines including the forkhead transcription factor forkhead/winged helix transcription factor gene (Foxp3), CTLA-4, TGF-beta, IL-10, TNF-alpha, and IFN-gamma. The RT-PCR results revealed that Fas expression preceded that of DcR3 during the early phases of tumorigenesis. Thereafter, the expression of DcR3 was up-regulated; however, the expression of Fas was down-regulated and eventually ceased. DcR3 and FasL were expressed and amplified simultaneously in muscle tumor. CTLA-4 expression was earlier than Foxp3, and both CTLA-4 and Foxp3 amplification and expression were consistent with that of DcR3. The results suggest that the elevated levels of DcR3, Foxp3, and CTLA-4 in tissue were positively correlated with tumor growth. The partial tumor immunoregulation inclined to negative modulation, and DcR3 may play an important role in inducing immunologic tolerance.
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PMID:Decoy receptor 3 overexpression and immunologic tolerance in hepatocellular carcinoma (HCC) development. 1909 53

Polymorphisms in cytokine genes responsible for inflammatory and immune responses are associated with risk of hepatocellular carcinoma (HCC) in high-risk Chinese population. Similar data in low-risk populations are lacking. A population-based case-control study of HCC was conducted including 120 HCC patients and 230 matched control subjects of non-Asian residents in Los Angeles County, California. Genetic variants in the interferon gamma (IFNgamma), tumor necrosis factor-alpha (TNFalpha), interleukin-2 (IL-2), IL-4, IL-6, IL-10, IL-12 and IL-18 genes were determined by Taqman assays. The logistic regression method was used to analyze the data. For T helper (Th) 1 genes (IFNgamma, IL-6 and IL-12), relative to the putative high-activity genotypes, individual low-activity genotypes were associated with statistically non-significant increases in HCC risk. The odds ratio (OR) was 1.53 [95% confidence interval (CI) = 0.53-4.39] for three versus zero low-activity genotypes. For Th2 cytokines (IL-4 and IL-10), low- versus high-activity genotypes were associated with statistically non-significant decreases in HCC risk. The OR was 0.64 (95% CI = 0.27-1.55) for two versus zero low-activity genotypes. When the Th1 and Th2 genotypes were examined simultaneously, the highest level of risk was observed in individuals jointly possessing the highest number of low-activity Th1 genotypes and the lowest number of low-activity Th2 genotypes. There was a roughly doubling of risk between these two extreme genetic profiles, which did not reach statistical significance (OR = 1.98, 95% CI = 0.50-7.84, P = 0.08). In contrast to high-risk Chinese, Th1 and Th2 genotypes did not impact in a major way on risk of HCC in USA non-Asians.
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PMID:Genetic polymorphisms in the cytokine genes and risk of hepatocellular carcinoma in low-risk non-Asians of USA. 1912 46

Two major distinct subsets of dendritic cells (DCs) are arranged to regulate our immune responses in vivo; 33D1(+) and DEC-205(+) DCs. Using anti-33D1-specific monoclonal antibody, 33D1(+) DCs were successfully depleted from C57BL/6 mice. When 33D1(+) DC-depleted mice were stimulated with LPS, serum IL-12, but not IL-10 secretion that may be mediated by the remaining DEC-205(+) DCs was markedly enhanced, which may induce Th1 dominancy upon TLR signaling. The 33D1(+) DC-depleted mice, implanted with syngeneic Hepa1-6 hepatoma or B16-F10 melanoma cells into the dermis, showed apparent inhibition of already established tumor growth in vivo when they were subcutaneously (sc) injected once or twice with LPS after tumor implantation. Moreover, the development of lung metastasis of B16-F10 melanoma cells injected intravenously was also suppressed when 33D1(+) DC-deleted mice were stimulated twice with LPS in a similar manner, in which the actual cell number of NK1.1(+)CD3(-) NK cells in lung tissues was markedly increased. Furthermore, intraperitoneal (ip) administration of a very small amount of melphalan (L: -phenylalanine mustard; L: -PAM) (0.25 mg/kg) in LPS-stimulated 33D1(+) DC-deleted mice helped to induce H-2K(b)-restricted epitope-specific CD8(+) cytotoxic T lymphocytes (CTLs) among tumor-infiltrating lymphocytes against already established syngeneic E.G7-OVA lymphoma. These findings indicate the importance and effectiveness of selective targeting of a specific subset of DCs, such as DEC-205(+) DCs alone or with a very small amount of anticancer drugs to activate both CD8(+) CTLs and NK effectors without externally added tumor antigen stimulation in vivo and provide a new direction for tumor immunotherapy.
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PMID:Induction of tumor-specific acquired immunity against already established tumors by selective stimulation of innate DEC-205(+) dendritic cells. 2022 97

Hepatitis, a common human disease, may be followed by severe liver injury, eventually leading to fatty liver, liver fibrosis and hepatocellular carcinoma. CD8 T cells are a double-edged sword in the response to infection with the hepatitis virus. On one hand, rapid activation of CD8 T cells is critically important for the elimination of the virus. On the other hand, in persistent viral infection, the activation of CD8 T cells substantially contributes to liver injury. The clinical course of hepatitis, thus, critically depends on mechanisms regulating the activity of CD8 T cells. In observations in human hepatitis and in mice infected with the lymphocytic choriomeningitis virus, the clinical course of hepatitis is modified by several immunological factors including neutralizing antibodies: RIG-I, TLRs, MyD88, interferon type I, TNF-alpha, MHC I, Tap, TCR, CD8, IL-2, IL-7, PD-1, IFN-I, IL-10, IFN-gamma, perforins, serotonin and iNOS (table 1) . Additional experimental effort is needed to understand the concerted interplay of those molecules in viral hepatitis of man and mice.
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PMID:Host mechanisms in viral hepatitis. 2046 Aug 87


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