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)

The murine melanoma cell line B16.F10 (H-2b) was used to study specific T cell responses that reject tumors. Stable B16 transfectants were established that express viral Ags, either the hepatitis B surface Ag (HBsAg) or the large tumor Ag (T-Ag) of SV40. B16 cells and their transfected sublines were CD40+ CD44+ but expressed no (or low levels of the) costimulator molecules CD154 (CD40L), CD48, CD54, CD80, and CD86. Surface expression of MHC class I (Kb, Db) and class II (I-Ab) molecules by B16 cells was low, but strikingly up-regulated by IFN-gamma. CD95 (Fas) and CD95 ligand (CD95L (FasL)) were "spontaneously" expressed by B16 cells growing in vitro in serum-free medium; these markers were strikingly up-regulated by IFN-gamma. B16 cells coexpressing CD95 and CD95L were irreversibly programmed for apoptosis. In vitro, noninduced B16 transfectants stimulated a specific IFN-gamma release response, but no cytolytic response (in a 4-h assay) in MHC class I-restricted CTL; in contrast, IFN-gamma-induced B16 targets were efficiently and specifically lysed by CTL. In vivo, B16 transfectants were specifically rejected by DNA-vaccinated syngeneic hosts through a T-dependent immune effector mechanism. The tumors showed evidence of massive apoptosis in vivo during the rejection process. The data suggest that CTL-derived IFN-gamma enhances an intrinsic suicide mechanism of these tumor cells in addition to facilitating lytic interactions of effectors with tumor targets.
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PMID:T cell-mediated, IFN-gamma-facilitated rejection of murine B16 melanomas. 967 Sep 68

Viral antigen-specific T cells are important for virus elimination. We studied the hepatitis B virus (HBV)-specific T cell response using flow cytometry. Three phases of HBV infection were studied: Group A, HBeAg (+) chronic hepatitis; Group B, HBeAb (+) HBV carrier after seroconversion; and Group C, HBsAb (+) phase. Peripheral T cells were incubated with recombinant HB core antigen (HBcAg), and intracytoplasmic cytokines were analysed by flow cytometry. HBcAg-specific CD4 and CD8 T cells were identified in all three groups and the number of IFN-gamma-positive T cells was greater than TNF-alpha-positive T cells. The frequency of IFN-gamma-positive CD4 and CD8 T cells was highest in Group C, compared with Groups A and B. No significant difference in the HBcAg-specific T cell response was observed between Group A and Group B. The HBcAg-specific CD8 T cell response was diminished by CD4 depletion, addition of antibody against human leucocyte antigen (HLA) class I, class II or CD40L. Cytokine-positive CD8 T cells without HBcAg stimulation were present at a high frequency (7 of 13 cases) in Group B, but were rare in other groups. HBcAg-specific T cells can be detected at high frequency by a sensitive flow cytometric analysis, and these cells are important for controlling HBV replication.
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PMID:High frequency of circulating HBcAg-specific CD8 T cells in hepatitis B infection: a flow cytometric analysis. 1147 5

Clearance of hepatitis B virus infection (HBV) infection implies a polyclonal vigorous T-helper 1 (Th1) and cytotoxic T-lymphocyte (CTL) response. Interleukin-18 (IL-18), a monokine that shares functional abilities with IL-12, is a potent inductor of interferon-gamma (IFN-gamma) by Th1 and natural killer (NK) cells. However, the role and regulation in HBV infection of IFN-gamma have not been defined. This study therefore sought to determine hepatitis B core antigen (HBcAg)-mediated regulation of IL-18 production in peripheral blood mononuclear cells (PBMCs) from healthy controls (HC) and patients with chronic hepatitis B (CHB) or acute hepatitis B (AHB); 31 HC, 27 patients with CHB and 8 patients with AHB infection were included in the study. HBcAg-mediated induction of IL-18 was determined by quantitative reverse transcription-polymerase chain reaction (RT-PCR) and specific enzyme-linked immunosorbent assay (ELISA). HBcAg induced IL-18 gene transcription and dose-dependent secretion of mature IL-18 protein in HC, CHB, and AHB. HBcAg-dependent IL-18 levels were abrogated by inhibition of Caspase-1, but not by blockade of CD40-CD154 interaction. Serum levels of IFN-gamma correlated inversely with viremia in patients with CHB (rho = - 0.54, P < 0.05), but not with serum levels of IL-12 or IL-18. Interestingly, in PBMCs of HBeAg-negative patients, HBcAg induced significantly higher amounts of IL-18 than in those of HBeAg-positive patients. A variant, lacking the histone-like arginine-rich domain, did not induce IL-18 in either HC or CHB in vitro. Taken together, these results indicate that HBcAg induces IL-18 secretion by induction of Caspase-1. Differential regulation in HBeAg-negative and positive patients suggests an important role of IL-18 in CHB infection.
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PMID:Hepatitis B core antigen is a potent inductor of interleukin-18 in peripheral blood mononuclear cells of healthy controls and patients with hepatitis B infection. 1285 6

CD40/CD154 interaction is essential for both humoral and cellular immune response. We investigated whether this interaction could be altered in patients with kidney failure who are known to present an impaired immune response. To that aim, we measured the levels of the soluble form of CD40 (sCD40), which is known to interfere with CD40/CD154 interaction, in 43 chronic renal failure patients, 162 hemodialysed patients, and 83 healthy donors. Uraemic and haemodialysed patients presented a three- and fivefold increase, respectively, of the antagonist soluble form of CD40 in their serum, when compared to healthy subjects. Serum sCD40 levels correlated with those of creatinine in uraemic non-haemodialysed patients. While sCD40 is widely excreted in urine of healthy individuals, it is not eliminated by dialysis sessions on classic membranes. The return to a normal kidney function in nine haemodialysed patients who received renal transplantation, leads to a rapid decrease of serum sCD40 levels. This natural sCD40 exhibited multimeric forms and was able to inhibit immunoglobulin production by CD154-activated B lymphocytes in vitro. Furthermore, the positive correlation we observed between the serum levels of sCD40 and the deficient response to hepatitis B vaccination in uraemic patients suggests that sCD40 also compromises the humoral response in vivo.
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PMID:Potential role of soluble CD40 in the humoral immune response impairment of uraemic patients. 1294 Nov 50

Cytotoxic T lymphocytes (CTL) are essential for control of primary infections by many pathogens and in particular by non-cytopathic viruses. It has been proposed that long-term maintenance of CTL memory and control of lymphocytic choriomeningitis virus (LCMV) is dependent upon the presence of T helper cells and interaction of antigen-presenting cells and CTL via CD40 and its ligand CD40L. However, we demonstrate here that CD40-CD40L interaction maintains CTL memory by induction of virus-specific antibodies. In fact, loss of CTL memory responses and spread of virus in mice lacking CD40 or its ligand is prevented by repetitive therapeutic injections of LCMV-specific antibodies. This indicates that antibodies are essential for long-term control of non-cytopathic virus and to maintain protective memory. Transfer of neutralizing antibodies or induction of antibodies by therapeutic vaccination within weeks after infection may therefore prove beneficial for the treatment of chronic virus infections such as HIV, hepatitis B, and hepatitis C. See accompanying article http://dx.doi.org/10.1002/eji.200324844
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PMID:Maintenance of memory CTL responses by T helper cells and CD40-CD40 ligand: antibodies provide the key. 1476 35

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

Engagement of CD154 on activated T cells with CD40 on antigen-presenting cells (APCs) potentiates adaptive immune responses in mammals. Soluble multimeric forms of CD154 have been used as an adjuvant or in immunotargeting strategies to enhance vaccine responses. The objective of our study was to examine the ability of duck CD154 (DuCD154) to enhance DNA vaccine responses in the duck hepatitis B model. Constructs were generated to express the functional domain of DuCD154 (tCD154), truncated duck hepatitis B virus (DHBV) core antigen (tcore) and chimera of tcore fused to tCD154 (tcore-tCD154). Expression in LMH cells demonstrated that all proteins were secreted and that tCD154 and tcore-tCD154 formed multimers. Ducks immunized with the plasmid ptcore-tCD154 developed accelerated and enhanced core-specific antibody responses compared to ducks immunized with ptcore or ptcore plus ptCD154. Antibody responses were better sustained in both ptcore-tCD154- and ptcore plus ptCD154-immunized ducks. Core-specific proliferative responses of duck peripheral blood mononuclear cells were enhanced in ducks immunized with ptcore-tCD154 or ptcore alone. This study suggests that the role of CD154 in the regulation of adaptive immune responses had already evolved before the divergence of birds and mammals. Thus, targeting of antigens to APCs with CD154 is an effective strategy to enhance DNA vaccine responses not only in mammalian species but also in avian species.
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PMID:Immunotargeting with CD154 (CD40 ligand) enhances DNA vaccine responses in ducks. 1689 98

To improve the investigation of the role of human memory B lymphocytes following hepatitis B virus (HBV) infection or vaccination, we developed a method to characterize circulating memory B cells specific to hepatitis B surface antigen (HBsAg). Our approach combined: (1) purification of CD19+ cells, (2) CD40-CD40L polyclonal stimulation, and (3) enumeration of memory B cells differentiated into anti-HBs antibody (Ab)-secreting cells (HBs-SCs) by a HBs-ELISPOT assay. In this way, HBs-SCs were detected in 17 HBsAg-vaccinated and nine HBV-immunized subjects including four individuals with serum anti-HBs Ab levels < 10 mIU/ml, but not in six controls. IgG+, IgA+ plus IgM+ HBs-SCs, representing 5-1736 cells/10(6) circulating B cells and 0.02-0.58% of total immunoglobulin-SCs generated by the B cell polyclonal stimulation, were counted by an Ig two-colour ELISPOT assay. In addition, anti-HBs Abs were found in 8/15 supernatants recovered from B cell cultures which contained HBs-SCs, suggesting that the HBs-ELISPOT assay is more reliable in tracking HBsAg-specific memory B cells than ELISA measurement of anti-HBs Abs secreted in supernatants. This new approach could be useful to explore the presence and the longevity of HBsAg-specific memory B cells in vaccinated and immunized subjects, in chronic HBV infection and after liver transplantation for HBV-related disease.
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PMID:Detection of memory B lymphocytes specific to hepatitis B virus (HBV) surface antigen (HBsAg) from HBsAg-vaccinated or HBV-immunized subjects by ELISPOT assay. 1695 61

The function of Ag-specific central (T(CM)) and effector (T(EM)) memory CD4+ T lymphocytes remains poorly characterized in vivo in humans. Using CD154 as a marker of Ag-specific CD4+T cells, we studied the differentiation of memory subsets following anti-hepatitis B immunization. Hepatitis B surface Ag (HBs)-specific memory CD4+T cells were heterogeneous and included T(CM) (CCR7+CD27+) and T(EM) (CCR7(-)CD27(+/-)). HBs-specific T(CM) and T(EM) shared the capacity to produce multiple cytokines, including IL-2 and IFN-gamma. Several years postimmunization, approximately 10% of HBs-specific memory CD4+ T cells were in cycle (Ki67+) and the proliferating cells were CCR7+. These results suggest that the model of functional specialization of T(CM) and T(EM) cannot be applied to protein vaccine Ags and support the concept that T(CM) are capable of self-renewal and contribute to maintain the pool of memory cells.
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PMID:Antigen-specific central memory CD4+ T lymphocytes produce multiple cytokines and proliferate in vivo in humans. 1711 95

CTLs are thought to be major effectors for clearing viruses in acute infections including hepatitis B virus (HBV). Persistent HBV infection is characterized by a lack of or a weak CTL response to HBV, which is thought to reflect tolerance to HBV antigens. In the present study, we found that alpha-galactosylceramide (alpha-GalCer), a ligand for Valpha14-positive NKT cells, strongly enhanced the induction and proliferation of HBV-specific CTLs by HBsAg. In HBsAg transgenic mice, which are thought to be tolerant to HBV-encoded antigens, administration of HBsAg or alpha-GalCer alone failed to induce HBsAg-specific CTLs, but they were induced by co-administration of both compounds. Furthermore, by limiting dilution analysis, we confirmed the existence of HBsAg-specific CTL precursors in the HBsAg transgenic mice immunized with HBsAg and alpha-GalCer. A blocking experiment using antibodies to cytokines and CD40 ligand showed that IL-2 and CD40-CD40L interaction mediate the enhancement of CTL induction caused by alpha-GalCer through NKT cell activation. Our results may open up a new method for clearing the virus from patients with persistent HBV infection.
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PMID:Role of Valpha14+ NKT cells in the development of Hepatitis B virus-specific CTL: activation of Valpha14+ NKT cells promotes the breakage of CTL tolerance. 1848 27


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