Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019163 (hepatitis B)
 38,309 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previously we showed that mononuclear cells from about half of human T-lymphotropic virus (HTLV)-seropositive persons exhibit spontaneous proliferation in vitro. We sought to determine if proliferation was associated with other immunologic changes characteristic of HTLV infection. The parameters assessed were (1) percentages of lymphocytes expressing CD4 and/or CD25 (interleukin-2 receptor), (2) serum levels of soluble CD25, (3) serostatus for other viruses, (4) anti-HTLV antibody levels, and (5) HTLV type determined by polymerase chain reaction or serologic reactivity with type-specific peptides. The proliferation+ HTLV (PROL+) group, proliferation HTLV (PROL-) group, and control group showed similar percentages of CD4+, CD25+, and CD4+CD25+ lymphocytes; serum levels of soluble CD25 were also similar. Antibodies to cytomegalovirus, hepatitis B core, and hepatitis C were present in similar proportions of PROL+ and PROL+ groups. However, a significant association was found between spontaneous proliferation and anti-HTLV antibody levels; sera from 67% of PROL+ persons, but only 18% of PROL- persons, required dilution to yield absorbance values within the linear range of the anti-HTLV antibody assay. In the PROL+ group, persons whose sera required the most dilution had proliferative responses significantly higher than those whose sera required no dilution. The PROL+ and PROL groups were similar with regard to the relative distribution of HTLV-I and HTLV-II infection. These findings indicate that HTLV-related spontaneous lymphocyte proliferation is related to levels of circulating anti-HTLV antibodies, and characterizes both HTLV-I and HTLV-II infection.
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PMID:Immunologic correlates of spontaneous lymphocyte proliferation in human T-lymphotropic virus infection. 167 16

We studied the immunoregulatory mechanisms of responsiveness and non-responsiveness to hepatitis B (HB) vaccine by analysing the influence of HB surface antigen (HBsAg) on lymphokine- or mitogen-stimulated peripheral lymphocytes from healthy volunteers. Stimulation with pokeweed mitogen (PWM) led to a reduced production of polyclonal IgG from responder cells compared to non-responder lymphocytes. PWM did not enhance the HBs-specific IgG production from responder lymphocytes when the cells were obtained at Day 10 after the last vaccination. A slight reduction of the proliferative response was observed when lymphocytes of non-responders were stimulated with phytohaemagglutinin (PHA) or concanavalin A (Con A). Production of HBs-specific antibodies was enhanced by incubating responder lymphocytes with interleukin-4 (IL-4). The HBs antigen itself did not modulate the expression of the CD23 B-cell differentiation antigen in unseparated lymphocytes. However, CD23 expression induced by low doses of IL-4 was markedly enhanced in an antigen-specific way. Our data indicate that HBs antigen enhances the lymphokine-induced CD23 expression, whereas the mitogen-induced CD23 expression is not affected. Lymphocytes obtained from non-responders exerted a reduced expression of CD25 surface antigen compared to responder lymphocytes. Exogeneous addition of IL-2 in the absence or presence of HBsAg induced a marked enhancement of the IL-2 receptor expression in responder lymphocytes. Furthermore, no significant modulation of CD25 expression was observed in non-responder lymphocytes.
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PMID:Effects of mitogens and lymphokines on the regulation of the immune response to HBs antigen in vitro. 214 40

The phytohemagglutinin (PHA) blastogenic response of normal healthy individuals was studied before and after vaccination with hepatitis B surface antigen. The PHA response was suppressed 2 d after the first dose of vaccine but was not affected by the second and the third doses of vaccine. The suppressed PHA blastogenic response on day 7 was not enhanced by the addition of interleukin-2 or indomethacin even though an increase in cell number expressing CD25 was observed. The removal of CD4+ or CD8+ cells enhanced the PHA response but only on days 2 or 4 and not at other sampling times, which suggests that the suppression is mediated by CD4+ or CD8+ cells. The addition of interleukin-2 alone or with PHA did not reverse the suppression at any time tested. In vitro induction of suppressor cells was performed and was blocked by the addition of indomethacin at the time of culture initiation.
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PMID:Phytohemagglutinin mitogenic response of normal individuals vaccinated with hepatitis B vaccine. 252 76

Young patients with Down's syndrome (DS) have high rates of infections, malignancies and autoimmune phenomena. Therefore, DS may be considered as a model of precocious, abnormal ageing of the thymus-dependent system in man. In DS children less than 6 years of age, the levels of serum immunoglobulins did not differ from healthy controls, but after that age, considerable hyper-IgG and -IgA were found. Furthermore, high levels of IgG1 and IgG3 have been found, whereas a progressive decline of IgG2 and IgG4 with age has been observed. The frequency of hepatitis B virus carriers even in the youngest age group is much higher among DS children. It has been reported that an IgG response was detectable in 75% of controls after HBsAg vaccination as compared to the 16.6% of DS patients. The presence of autoantibodies against human thyroglobulin did show a positive association with HB Virus Ag carriers, but only in the oldest DS subjects. Natural antibodies against intestinal antigens are low, while in the presence of cow's milk, abnormally high titres against casein and beta-lactoglobulin were present. High levels of IgG antibodies against gliadin have been observed. In spite of a normal percentage of CD3- and CD2-positive lymphocytes, a high proportion of cells express low-avidity receptors for sheep erythrocytes. Although the proportion of CD4+ T-lymphocyte helper-cells is normal, a marked imbalance in the CD4+ subpopulations has been documented. The percentage of suppressor-cytotoxic CD8+ lymphocytes is markedly increased. The responses to phytohemagglutinin and concanavalin A are within the normal range in the first decade of life and decline progressively thereafter. A recent study reported defective proliferative response to allo-mixed lymphocyte culture, with decreased expression of the membrane CD25, low secretion of interleukin 2 in the supernatant and depressed allo-specific cytotoxic activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Immunological features of Down's syndrome: a review. 812

Dysregulation of T-cell receptor (TCR) alphabeta bearing lymphocytes and an increase in Vdelta1+ gammadelta T cells are typical features of HIV-1 infection. However, the role of gammadelta T cells remains unclear. Therefore, peripheral blood mononuclear cells (PBMC) of 103 HIV-1-infected patients were investigated with respect to expression of Vdelta1. These results were compared to the Vdelta1 expression of bone marrow mononuclear cells (BMMC). In contrast to healthy controls, Vdelta1+ cells dominated among both PBMC and BMMC in HIV-1-infected patients. Analysis of the coexpression of CD25, CD8, HLA-DR and CD45RO revealed a high prevalence of Vdelta1/CD45RO and Vdelta1/HLA-DR double-positive PBMC only in HIV-1-infected patients but not in healthy donors. Furthermore, analysis of the gammadelta TCR repertoire in patients infected with hepatitis B virus, hepatitis C virus, herpes simplex virus (HSV)-1 and HSV-2 showed that the selective enhancement of Vdelta1+ cells was restricted to HIV infection and not observed in other virus diseases. Our data provide further support for the involvement of gammadelta T cells in immunosuppression and progression of HIV infection.
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PMID:Increase in Vdelta1+ gammadelta T cells in the peripheral blood and bone marrow as a selective feature of HIV-1 but not other virus infections. 953 41

CD4(+) T cells play a major role in the host defense against viruses and intracellular microbes. During the natural course of such an infection, specific CD4(+) T cells are exposed to a wide range of antigen concentrations depending on the body compartment and the stage of disease. While epitope variants trigger only subsets of T-cell effector functions, the response of virus-specific CD4(+) T cells to various concentrations of the wild-type antigen has not been systematically studied. We stimulated hepatitis B virus core- and hepatitis C virus NS3-specific CD4(+) T-cell clones which had been isolated from patients with acute hepatitis during viral clearance with a wide range of specific antigen concentrations and determined the phenotypic changes and the induction of T-cell effector functions in relation to T-cell receptor internalization. A low antigen concentration induced the expression of T-cell activation markers and adhesion molecules in CD4(+) T-cell clones in the absence of cytokine secretion and proliferation. The expression of CD25, HLA-DR, CD69, and intercellular cell adhesion molecule 1 increased as soon as T-cell receptor internalization became detectable. A 30- to 100-fold-higher antigen concentration, corresponding to the internalization of 20 to 30% of T-cell receptor molecules, however, was required for the induction of proliferation as well as for gamma interferon and interleukin-4 secretion. These data indicate that virus-specific CD4(+) T cells can respond to specific antigen in a graded manner depending on the antigen concentration, which may have implications for a coordinate regulation of specific CD4(+) T-cell responses.
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PMID:Different levels of T-cell receptor triggering induce distinct functions in hepatitis B and hepatitis C virus-specific human CD4(+) T-cell clones. 1148 23

Adoptive therapy with antigen-specific T cells is a potential treatment against cancers and viral diseases. To establish a system to modify the genes of these cells to increase their effectiveness, we examined whether the combined use of retroviral vector, which only infects dividing cells, and in vitro sensitization of T cells with antigen-loaded dendritic cells (DCs) could selectively modify antigen-specific T cells with a bcl-2 gene. Human CD4(+) T cells were used as target cells. Autologous DCs transfected with genes of hepatitis B virus (HBV) stimulated a specific T cell proliferation. Importantly, these proliferating T cells were selectively transduced by a bcl-2-retrovirus, and CD25(+) T cells isolated from them contained higher levels of integrated provirus. To select bcl-2-transduced, activated T cells, cells were subjected to interleukin-2 (IL-2) withdrawal. In contrast to CD25(-) and mock-infected CD25(+) T cells, 70% of CD25(+) T cells transduced with bcl-2-retrovirus survived IL-2 withdrawal. These surviving T cells were demonstrated to contain integrated bcl-2 provirus and exhibited HBV-specific proliferation and interferon-gamma secretion. In addition, bcl-2 overexpression protected HBV-specific T cells from transforming growth factor (TGF)-beta-induced cell death. These results demonstrate the feasibility of our strategy in the generation of genetically modified antigen-specific CD4(+) T cells and show that bcl-2-transduced antigen-specific T cells survive IL-2 withdrawal and TGF-beta-induced apoptosis.
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PMID:Selective modification of antigen-specific CD4(+) T cells by retroviral-mediated gene transfer and in vitro sensitization with dendritic cells. 1213 48

We have previously reported several CTL epitopes derived from the hepatitis B viral X Ag (HBx). In this study, we evaluated whether HBx-specific CTLs can be effectively used in adoptive cancer immunotherapy. To validate the possibility, four peptides containing a HLA-A2.1-restricted binding consensus motif were identified from the HBx protein and tested for their ability to activate CTL from PBMCs isolated from chronic carriers of HBV (n = 12). We selected two highly potent epitopes, HBx 52-60 (HLSLRGLFV) and HBx 115-123 (CLFKDWEEL), that are capable of inducing Ag-specific cytotoxic T cells in patient PBMCs. For adoptive immunotherapy using HBx-specific CTLs, we generated CTL clones restricted to the HBx 52-60 or HBx 115-123 peptide using a limiting dilution technique. LC-46, an HBx 52-60-specific clone, is CD62L(-)CD69(+)CD45RO(+)CD45RA(-)CD25(dim) and is stained by IFN-gamma (approximately 92%), IL-2 (30%), and TNF-alpha (56%), but not by IL-5, IL-10, IL-12, or TNF-beta, indicating that the cells are fully activated T cytotoxic 1-type cells. When LC-46 cells were adoptively transferred into xenografted nude mice bearing human hepatomas expressing HLA-A2.1 molecules and intracellular HBx proteins, the tumors were eradicated. Taken together, our data provide solid evidence for the feasibility of adoptive immunotherapy with HBx-sensitized CTLs in hepatitis disease, including hepatocellular carcinoma (HCC).
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PMID:Tumor eradication by hepatitis B virus X antigen-specific CD8+ T cells in xenografted nude mice. 1253 74

Transforming growth factor-beta (TGF-beta), found at the site of most tumors, has been recognized as one of the mechanisms involved in tumor immunological escape. To evaluate its impact on adoptive immunotherapy against cancer, we examined the susceptibility of tumor-specific T cells to TGF-beta in the setting of these T cells being prepared for adoptive transfer. Hepatitis B virus (HBV)-specific CD4(+) T cells were ex vivo generated by activating with HBV-transfected dendritic cells and selecting with antibodies to CD25 activation molecules, and then expanded with antibodies to CD3/CD28. These T cells expressed higher levels of the type II TGF-beta receptor than nai;ve T cells and exhibited enhanced apoptosis when exposed to TGF-beta. The underlying apoptotic pathway was linked to the dissipation of the mitochondrial inner membrane potential and activation of caspase-9. The absence of caspase-8 activity in TGF-beta-treated T cells suggests that the death receptor system may not be involved in this type of apoptosis. Interleukin-2 (IL-2), which is concomitantly administered with tumor-specific T cells in adoptive immunotherapy, was unable to protect HBV-specific CD4(+) T cells from the pro-apoptotic effect of TGF-beta when added simultaneously with TGF-beta. Interesting, IL-2-pretreated T cells displayed the type II TGF-beta receptor at lower levels and were more resistant to TGF-beta. Together, our findings indicate that the effectiveness of adoptive cancer immunotherapy may be impaired by tumor-derived TGF-beta and appropriate manipulation of exogenous IL-2 might overcome this hurdle.
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PMID:Transforming growth factor-beta induces apoptosis in antigen-specific CD4+ T cells prepared for adoptive immunotherapy. 1260 Jul 43

Nonresponsiveness against hepatitis B vaccination has been described in 4-10% of immunized subjects. We have explored the specific cell response to hepatitis B surface antigen by analyzing: PBMC proliferation, cytokine production (Th1, Th2 profiles, and TGF-beta), and activation molecules on Th cells. A poor proliferative response was demonstrated in nonresponders (P < 0.05). T cells from responders produced all tested cytokines (P < 0.01), in contrast with nonresponders subjects (P < 0.05). Expression of CD69 and CD25 was diminished in T cells from nonresponders (P < 0.01). A reduced expression of CD40L was also detected in T cells from nonresponders (P < 0.01). An elevated correlation coefficient was observed between CD40L on CD4+ cells and antibody production. These results suggest an overall inability of T cells to be activated which could be consistent with potential differences in antigen presentation. In conclusion, our results suggest that an altered Th response may be a consequence of inappropriate early activation events.
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PMID:The nonresponse to hepatitis B vaccination is associated with impaired lymphocyte activation. 1526 91


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