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

HLA-A2.1-/HLA-DR1-transgenic H-2 class I-/class II-knockout mice were created and their immunological potential evaluated in response to hepatitis B DNA vaccine. Every single immunized mouse developed hepatitis B virus-specific antibodies, HLA-DR1-restricted helper, and HLA-A2.1-restricted cytolytic T cell responses directed at the same immunodominant epitopes as those identified in naturally infected or vaccinated humans. These mice were specifically protected against a hepatitis B-recombinant vaccinia virus infection with a 10,000-fold or more reduction of the virus load at day 4 post-challenge. These mice represent a unique in vivo experimental model for human immune function studies without any interference with mouse MHC response which dwarfed the prediction of human responses. Furthermore, they enable the complete monitoring of immune adaptative responses for preclinical screening of candidate vaccines.
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PMID:A mouse model of human adaptive immune functions: HLA-A2.1-/HLA-DR1-transgenic H-2 class I-/class II-knockout mice. 1546 58

To test whether simple expression units used in DNA vaccines can generate immunogenic, MHC class I-binding epitopes by translating other than the primary open reading frame (ORF), we constructed a vector (pCI/SX) that encodes the small hepatitis B surface Ag in the primary ORF, and a C-terminal fragment (residue 344-832) of the polymerase (Pol) in an alternative (out-of-frame) reading frame. pCI/SX efficiently primed multispecific, HLA-A2-restricted CD8+ T cell responses to epitopes of hepatitis B surface Ag and of Pol (Pol3, Pol(803-811)). Pol3-containing products generated from pCI/SX were detected only by T cell assays, but not by biochemical assays. Priming Pol-specific T cell responses to epitopes generated from alternative ORFs depended on promoter sequences that drive transcription in the DNA vaccine (human CMV-derived promoter sequences being more efficient than SV40-derived promoter sequences). Human CMV promoter-driven Pol constructs encoding different Pol fragments in primary or alternative reading frames elicited comparable levels of Pol3-specific T cell responses. We confirmed efficient T cell priming to epitopes from alternative ORFs by constructing DNA vaccines that encode an SV40-derived cT(1-272) protein fused either in frame or out of frame with an immunogenic OVA fragment (OVA(18-385)). Similar OVA-specific CD8+ T cell responses were primed by both alternative vaccine constructs. Hence, DNA vaccine-stimulated T cell responses to epitopes generated from alternative ORFs seem to be a regular event, although its biological role and risks are largely unexplored.
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PMID:Translation from cryptic reading frames of DNA vaccines generates an extended repertoire of immunogenic, MHC class I-restricted epitopes. 1581 88

A polyepitopic CD8+ T-cell response is critical for the control of hepatitis B virus (HBV) infection. The HBV X protein (HBx) is a multifunctional protein that is important for the viral life cycle and for host-virus interactions. The aim of this study was to analyze the immunogenicity and dominance of various HLA-A*0201-restricted HBx-derived epitopes. For this purpose, we immunized HLA-A*0201-transgenic mice with HBx-derived peptides and DNA. This is a powerful model for studying the induction of HLA-A*0201-restricted immune responses in vivo, as these mice possess a cytotoxic T lymphocyte (CTL) repertoire representative of HLA-A2.1 individuals. We used cytotoxic tests and enzyme-linked immunosorbent spot (ELISPOT) assays to study the induction of specific cytotoxic and interferon (IFN)-gamma-secreting T cells. This allowed us to classify the HBx epitopes according to their T-cell activation capacity. After endogenous processing of the antigen synthesized in vivo after DNA-based immunization, we found that the HBx-specific T-cell response is targeted against one immunodominant epitope. Furthermore, following peptide immunization, we identified six additional novel subdominant T-cell epitopes. Inclusion of well-characterized epitopic sequences of HBx in a new vaccine for chronic HBV infections could help to broaden the T-cell response.
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PMID:In vivo hierarchy of immunodominant and subdominant HLA-A*0201-restricted T-cell epitopes of HBx antigen of hepatitis B virus. 1582 Jan 53

A patient with cervical non-Hodgkin lymphoma was treated with chemotherapy. Fourteen months after the diagnosis of the lymphoma, an endometrial adenocarcinoma was detected as a secondary malignant tumor. The patient was treated with surgery followed by radiotherapy. Approximately 7 years after the diagnosis of endometrial cancer, vaginal invasive squamous cell carcinoma was diagnosed as the third primary malignancy, and a second-line palliative radiotherapy was applied. Seven months after the last radiotherapy, postradiational sarcoma in the vagina was diagnosed. Congenital and acquired immune system disorders, viral oncogenes, and various human leukocyte antigen (HLA) types were investigated. Total blood count and lymphocyte subset analysis were performed, and CD4+ lymphopenia was detected. Serologic tests were carried out for human immunodeficiency virus, hepatitis B virus, human papillomavirus, Epstein-Barr virus, and herpes simplex virus infection. Epstein-Barr virus viral capsid antigen IgG was found positive. Low-risk human papillomavirus panel was detected by Hybrid Capture method in the cervical smear. The HLA investigation revealed HLA-A2, HLA-A3, HLA-B57, HLA-B35, HLA-B4, HLA-B6, HLA-DR3, HLA-DR1, HLA-DR51, HLA-DR52, HLA-DQ6(1), and HLA-DQ7(3). The patient died because of the disease.
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PMID:A case with multiple gynecological malignancies. 1582 28

Immunization with plasmid DNA represents an attractive method for increasing cellular immune responses against cancer antigens. The safety and immunologic response of a plasmid encoding the MART-1 melanocyte differentiation antigen was evaluated in 12 patients with resected melanoma at risk for relapse. As a control, patients were also administered a plasmid encoding hepatitis B surface antigen (HBsAg). After establishing immunologic activity of the vaccines in mice, groups of three to six HLA-A2-positive patients were enrolled into one of three cohorts in which they received intramuscular injections of the MART-1 plasmid into the right deltoid and the HBsAg plasmid into the left deltoid at doses of 0.1, 0.3, or 1.0 mg on days 1, 43, 85, and 127. Injections were well tolerated. Toxicity was limited to grade 1 pain and injection site tenderness. Systemic toxicity was not observed. Although baseline MART-1-specific lymphoproliferative and ELISPOT responses were evident, no patient manifested increases after injection of the MART-1 plasmid. Furthermore, changes in MART-1-specific precursors were not evident after immunization as assessed by an in vitro stimulation assay. No patients manifested a lymphoproliferative response to HBsAg antigen, and significant antibody responses to HBsAg were also not observed. Although injections were safe, the authors could not show significant immunologic responses to plasmid encoding MART-1 or HBsAg using the dose, schedule, and route of administration applied. This study underscores species differences in the ability to respond to plasmid immunogens.
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PMID:Phase I study of a plasmid DNA vaccine encoding MART-1 in patients with resected melanoma at risk for relapse. 1600 Sep 57

To improve the immunogenicity of epitopes derived from Gag proteins of simian immunodeficiency virus (SIV) and from the envelope (Env) protein of human immunodeficiency virus type 1 (HIV-1), we have designed hybrid DNA vaccines by inserting sequences encoding antigenic domains of SIV and HIV-1 into the hepatitis B virus envelope gene. This gene encodes the hepatitis B surface antigen (HBsAg) capable of spontaneous assembly into virus-like particles that were used here as carrier. Injections of hybrid vectors encoding B-cell epitopes from the gp41 and the gp120 envelope proteins of HIV-1 induced specific humoral responses in BALB/c mice. Furthermore, high frequencies of IFN-gamma-secreting CD8+ T cells specific for various antigenic determinants of SIV-Gag were observed after intramuscular injections of hybrid DNA vectors in BALB/c mice. Genetic immunization of HLA-A2.1-transgenic mice with HIV-Env/HBsAg-encoding DNA generated a strong CTL response and IFN-gamma-secreting CD8+ T lymphocytes specific for HIV-1 envelope-derived peptide. H-2d-restricted HBs-specific T-cell responses dominated over SIV-Gag responses in BALB/c mice whereas HLA-A2-restricted HIV-Env response was enhanced after fusion with HBsAg. These data demonstrate that different B and T-cell epitopes of vaccine-relevant viral antigens can be expressed in vivo as fusion proteins with HBsAg but that the optimal immunogenicity may differ strikingly between individual epitopes.
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PMID:In vivo induction of cellular and humoral immune responses by hybrid DNA vectors encoding simian/human immunodeficiency virus/hepatitis B surface antigen virus particles in BALB/c and HLA-A2-transgenic mice. 1616 38

Immunogenic peptide-based vaccines can raise significant cellular immune responses. Although cytotoxic T lymphocytes (CTL) peptide epitopes are generally poor immunogens, heat shock protein 70 from Mycobacterium tuberculosis (TBhsp70) can overcome this problem since it is a potent adjuvant that links innate and adaptive immune responses. Our goal is to use TBhsp70 as an adjuvant for development of therapeutic vaccines for chronic Hepatitis B virus infection (HBV). To this end, we genetically fused the HBV core 18-27 peptide (HBcAg((18-27))) as a CTL epitope to the C-terminus of TBhsp70 and expressed the resulting protein in methylotropic yeast Pichia pastoris GS115. At the same time, the TBhsp70-HBcAg((18-27)) peptide complex was reconstituted in vitro. We investigated whether TBhsp70-peptide complex and TBhsp70-peptide fusion protein could generate antigen specific CTL responses in vitro. Dendritic cells (DC) from HLA-A2(+) chronic HBV infection and healthy control pulsed with two vaccines were studied phenotypically by FACS analyses and functionally by cytokine release, and HBV-specific CTL response. Our results demonstrate that two vaccines can activate DC of chronic HBV infection and healthy control by upregulation CD40 and CD86, high production of IL-12p70 and TNF-alpha. Furthermore, autologous T cells with DC stimulated by two vaccines can produce IFN-gamma and generate HBV-specific CTL response. However, capacity for CTL response and cytokines production from HBV infections remained inferior to that of healthy controls. Thus, the strategy of utilizing TBhsp70 may provide a novel design for the development of prophylactic and therapeutic vaccines.
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PMID:Novel vaccines for the treatment of chronic HBV infection based on mycobacterial heat shock protein 70. 1644 13

We reported previously that heat shock protein gp96 and its N-terminal fragment were able to stimulate CTL expansion specific for a HBV peptide (SYVNTNMGL) in BALB/c mice. Here we characterized the adjuvant effects of gp96 on human HLA-A2 restricted T cells. Full-length gp96 isolated from healthy human liver and recombinant fragments both from prokaryotic cells and eukaryotic cells were analyzed for their ability to stimulate maturation of human dendritic cells. It was found that in vitro these proteins were capable of maturating human monocyte-derived dendritic cells (MDDC) isolated from healthy donors as well as from HBV-positive, hepatocellular carcinoma (HCC) patients. In HLA-A2.1/Kb transgenic mice, gp96 and the recombinant fragments were found to augment CTL response specific for the HBcAg(18-27) FLPSDFFPSV peptide of hepatitis B virus.
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PMID:Effects of heat shock protein gp96 on human dendritic cell maturation and CTL expansion. 1663 May 54

Prostate stem cell antigen (PSCA) and prostate-specific antigen (PSA) are overexpressed in most prostate cancers. PSCA- and PSA-derived, HLA-A2 binding peptides are specific targets for T-cell responses in vitro. A phase I/II trial was performed to demonstrate feasibility, safety and induction of antigen-specific immunity by vaccination with dendritic cells (DC) presenting PSCA and PSA peptides in patients with hormone- and chemotherapy-refractory prostate cancer. Patients received 4 vaccinations with a median of 2.7 x 10(7) peptide-loaded mature DC s.c. in biweekly intervals. Clinical responses were assessed 2 weeks after the 4th vaccination. Immune monitoring was performed by DTH and HLA multimer analysis. Twelve patients completed vaccination without relevant toxicities. Six patients had stable disease after 4 vaccinations. One patient had a complete disappearance of lymphadenopathy despite rising PSA. Four patients with SD and 1 progressor developed a positive DTH after the 4th vaccination. With a median survival of all patients of 13.4 months, DTH-positivity was associated with significantly superior survival (p = 0.003). HLA tetramer analysis detected high frequencies of peptide-specific T cells after 2 vaccinations in 1 patient who was also the sole responder to concomitant hepatitis B vaccination as an indicator of immune competence and survived 27 months after start of vaccination. Vaccination with PSA/PSCA peptide-loaded, autologous DCs may induce cellular responses primarily in immunocompetent patients, which appear to be associated with clinical benefit. Testing of DC-based vaccination is warranted for patients at earlier stages of prostate cancer.
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PMID:Vaccination of advanced prostate cancer patients with PSCA and PSA peptide-loaded dendritic cells induces DTH responses that correlate with superior overall survival. 1697 30

Inhibition of hepatitis B virus (HBV) replication and viral clearance from an infected host requires both the innate and adaptive immune responses. Expression of interferon (IFN)-inducible proteasome catalytic and regulatory subunits correlates with the IFN-alpha/beta- and IFN-gamma-mediated noncytopathic inhibition of HBV in transgenic mice and hepatocytes, as well as with clearance of the virus in acutely infected chimpanzees. The immunoproteasome catalytic subunits LMP2 and LMP7 alter proteasome specificity and influence the pool of peptides available for presentation by major histocompatibility complex class I molecules. We found that these subunits influenced both the magnitude and specificity of the CD8 T-cell response to the HBV polymerase and envelope proteins in immunized HLA-A2-transgenic mice. We also examined the role of LMP2 and LMP7 in the IFN-alpha/beta- and IFN-gamma-mediated inhibition of virus replication using HBV transgenic mice and found that they do not play a direct role in this process. These results demonstrate the ability of the IFN-induced proteasome catalytic subunits to shape the HBV-specific CD8 T-cell response and thus potentially influence the progression of infection to acute or chronic disease. In addition, these studies identify a potential key role for IFN in regulating the adaptive immune response to HBV through alterations in viral antigen processing.
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PMID:Role of immunoproteasome catalytic subunits in the immune response to hepatitis B virus. 1707 20


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