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Biomedical subjects

B Wahren

Publications and source records attributed to B Wahren.

At least 55 records · Page 3Linked to original sources
PubMed2000

Growth phenotypes of cytomegalovirus isolates do not correlate with glycoprotein B, major immediate early genotypes or antiviral sensitivity.

Human Cytomegalovirus (CMV) is generally described from in vitro experiments as a slowly replicating virus. A doubling time of one day in blood, however, has been shown in vivo. The growth phenotypes of CMV isolates and laboratory strains were studied in human fibroblasts. The viruses were found to replicate either rapidly or slowly. Comparison of CMV protein expression in lung and foreskin fibroblast cultures showed that two tissue culture adapted CMV strains (AD169 and Towne) and 3 clinical isolates belonged to the rapidly replicating viruses, whereas another 3 clinical isolates replicated slowly. CMV antigen concentrations were 6-fold and virus yields were 10-1000-fold higher for the rapidly replicating viruses than for the slow replicators. The antigen expression of two slowly replicating isolates was enhanced after 20 passages compared to the isolates at passage 5, but it was not as efficient as that of strain Towne. Slow or fast replication was related neither to major immediate early gene exon 4, and gB genotypes, nor to antiviral susceptibility. Proteins of the beta cascade may contribute to differences in the replication rate of CMV isolates.

Antiviral Agents↗
PubMed1999

Dose-response resistance to HIV-1/MuLV pseudotype virus ex vivo in a hairpin ribozyme transgenic mouse model.

We have investigated the efficacy of a hairpin ribozyme targeting the 5' leader sequence of HIV-1 RNA in a transgenic model system. Primary spleen cells derived from transgenic or control mice were infected with HIV-1/MuLV pseudotype virus. A significantly reduced susceptibility to infection in ribozyme-expressing transgenic spleen cells (P = 0.01) was shown. Variation of transgene-expression levels between littermates revealed a dose response between ribozyme expression and viral resistance, with an estimated cut off value below 0.2 copies of hairpin ribozyme per cell. These findings open up possibilities for studies on ribozyme efficacy and anti-HIV-1 gene therapy.

Animals↗
PubMed1999

Immune responses in asymptomatic HIV-1-infected patients after HIV-DNA immunization followed by highly active antiretroviral treatment.

Intensive chemotherapy is capable of reducing the viral load in HIV-1-infected individuals while infected cells are still present. A special property of DNA immunization is to induce both new CTL and Ab responses. We evaluated the possibility of inducing new immune responses in already infected individuals by means of DNA constructs encoding the nef, rev, or tat regulatory HIV-1 genes. Significant changes in viral loads and CD4+ counts were observed in four patients who started highly active antiretroviral treatment (HAART) during the immunization study. The DNA immunization induced Ag-specific T cell proliferation, which persisted up to 9 mo after the last DNA injection, and cytolytic activities but did not, by itself, reduce viral load. Increased levels of CTL precursor cells were induced in all nine DNA-immunized patients. The profile of IFN-gamma secretion observed when human PBMC were transfected with the nef, rev, and tat DNA resembled that found in the CTL activity (nef > tat > rev). Ab responses that occurred after immunizations were of a low magnitude. In accordance with the high IL-6 production induced by the nef DNA plasmid, IgG titers were highest in patients immunized with nef DNA. The initiation of HAART appears to contribute to the induction of new HIV-specific CTL responses, but by itself did not cause obvious re-induction of these activities.

AIDS Vaccines↗
PubMed1999

Immunological responses to envelope glycoprotein 120 from subtypes of human immunodeficiency virus type 1.

The outer envelope glycoprotein (gp120) from subtypes A-E of HIV-1 was purified using a specific high mannose-binding lectin, Galanthus nivalis agglutinin. All isolates were grown in peripheral blood lymphocyte cells in order to avoid selection in cell lines. A comparison of the reactivities of the envelope proteins was made using sera from patients infected with the different subtypes. In this study, the B and C subtype envelope glycoproteins showed the strongest immunological reactivity, when reacted with sera from patients infected with the same subtype of virus. On the other hand, sera of patients infected with subtype A or C virus had the strongest and broadest reactivities, to envelope glycoproteins of many subtypes. The purified gp120 proteins from all five subtypes stimulated mononuclear cells from HIV-1 (subtype B)-infected patients, indicating conserved T cell-activating epitopes. The immunological reactivities indicate that strong antigenicity does not always predict the broadest immunogenicity of an envelope glycoprotein. Glycoprotein 120 from foreign subtypes may serve to induce strong cross-reactive immune responses.

Amino Acid Sequence↗
PubMed1999

Therapeutic immunisation with recombinant gp160 in HIV-1 infection: a randomised double-blind placebo-controlled trial. Nordic VAC-04 Study Group.

BACKGROUND: The immune system's ability to scavenge and destroy detrimental HIV-1 products has an important effect on virion production and the course of infection. In earlier trials of therapeutic immunisation with envelope protein recombinant gp160 (rgp160) we observed a transient positive effect on CD4-lymphocyte counts. This randomised placebo-controlled study investigated whether our preliminary findings represented a potential for a more benign clinical course. METHODS: 835 HIV-seropositive patients from 20 centres in Sweden, Norway, and Finland with CD4-cell counts above 200/microL were randomly assigned to receive 160 microg rgp160 or placebo (alum adjuvant alone) every 3 months for 3 years after an induction period, as well as optimum available treatment. Analyses were by intention to treat. FINDINGS: 63 of 416 vaccine-group patients and 61 of 419 placebo-group patients reached a primary clinical endpoint (AIDS-defining event or death); the time to first clinical endpoint did not differ between the groups (p=0.864). Significantly fewer vaccine-group patients than placebo-group patients reached the primary immunological endpoint of a decrease of more than 30% from baseline CD4-cell count (157 vs 189, p=0.03). A higher proportion of the vaccine group had CD4-cell counts higher than baseline at 6 months (167 vs 133, p=0.014). HIV-1-specific T-cell immune reactivity was induced in all vaccine recipients studied. No severe adverse events associated with the vaccine were noted during the study. There were significantly fewer deaths among the vaccine recipients than among the placebo-group patients at 2 years, but not at the end of the study. INTERPRETATION: Therapeutic immunisations with rgp160 have a modest effect on CD4-cell counts, but this treatment alone did not lead to clinical benefit when given in addition to best clinical practice at the time of the trial. Immunisation in conjunction with antiretroviral therapy was also effective, which strongly suggests that a combination with highly active therapy would improve the total effect.

AIDS Vaccines↗
PubMed1999

Induction of mucosal IgA by a novel jet delivery technique for HIV-1 DNA.

Novel ways of delivering plasmid DNA to elicit humoral IgA, IgG and cell-mediated immune responses in mice were investigated. Intraoral administration of DNA in the cheek, using a jet immunization technique, elicited the highest IgA mucosal responses. Intranasal immunization gave strong mucosal IgA responses and persistent systemic IgG. Immunoglobulin isotype analysis revealed an IgG1 profile for intramuscular tongue and gene gun immunizations and an IgG2a profile following oral jet injection and intranasal application. The route of delivery was of importance for the characteristics and quality of the mucosal immune response following DNA immunization. For DNA vaccine delivery, the intraoral jet injection technique has the advantages of being a simple and rapid way of administering the DNA in solution and of provoking specific mucosal IgA when administered in the mucosal associated lymphoid tissue.

Administration, Intranasal↗
PubMed1999

Eukaryotic expression of enzymatically active human immunodeficiency virus type 1 reverse transcriptase.

Reverse transcriptase of human immunodeficiency virus type I is a vitalenzyme in the HIV-1 replication cycle and an attractive target of attempts to arrest a primary viral infection. We designed a vector for eukaryotic expression of the 66 kDa subunit of reverse transcriptase under the control of the immediate early cytomegalovirus promoter. Efficient transient expression of the 66 kDa subunit of reverse transcriptase was achieved in a variety of cells. Immunostaining of the transfected cells revealed the cytoplasmatic localization of reverse transcriptase. Reverse transcriptase activity was detected in all transfected cell lines. Injection of this plasmid encoding the 66 kDa subunit of reverse transcriptase into mice resulted in strong reverse transcriptase-specific immune responses indicating that the 66 kDa subunit of reverse transcriptase is expressed in vivo. Sera from DNA-immunized mice inhibited reverse transcription in vitro.

3T3 Cells↗
PubMed1999

[Promising experiments with DNA vaccine against HIV. A complete eradication of the virus is a formidable task].

The past few years have witnessed encouraging progress in experimental HIV vaccination. Several new vaccine candidates have been shown to elicit immune response and provide protection in animals, and the first immunotherapy trials in humans have been reported. Difficulties remain to be overcome, however. No consensus exists regarding trials in humans. Some researchers and clinicians believe that we must await a vaccine demonstrably and reproducibly effective in animals. Immunogenicity alone is considered insufficient to ensure clinical protection. Others consider animal experiments valuable, but believe that actual trials should be made in humans in the target population. Trials are urgently needed in countries with high transmission rates, even if optimal efficacy cannot be guaranteed.

Animals↗
PubMed1999

Antigen-specific immunosuppression: nasal tolerance to P0 protein peptides for the prevention and treatment of experimental autoimmune neuritis in Lewis rats.

Experimental autoimmune neuritis (EAN) is an autoimmune inflammatory demyelinating disease of the peripheral nervous system (PNS), and represents an animal model of the human Guillain-Barré syndrome (GBS). In this study, we report that nasal administration of the neuritogenic peptide 180-199 and of the cryptic peptide 56-71 of the rat neuritogenic P0 protein of peripheral nerve myelin prevents EAN and attenuates ongoing EAN. Both peptides effectively decreased the severity and shortened clinical EAN. Both a prophylactic and a therapeutic approach proved to be beneficial. These effects were associated with T and B cells hyporesponsiveness to the peptide antigens, reflected by downregulated Th1 cell responses (interferon-gamma secretion) and macrophage function, whereas Th2 cell responses (IL-4 secretion) and transforming growth factor-beta mRNA expression were upregulated.

Administration, Intranasal↗
PubMed1999

Induction of experimental autoimmune neuritis in CD4-8-C57BL/6J mice.

The C57BL/6J mice strain is known to be reputedly resistant to induction of experimental autoimmune neuritis (EAN), an animal model of Guillain-Barré syndrome in humans. Here we describe the induction of EAN in mice of the C57BL/6J background by transfer into naive syngeneic recipients bovine peripheral nerve myelin (BPM)-primed donor lymph node cells that had been stimulated in vitro with the bovine peripheral nervous system (PNS) myelin P2 protein peptide 57-81 followed by challenge with BPM, Freund's complete adjuvant and pertussis toxin. EAN was more severe, both clinically and histologically, and accompanied by extensive infiltration of inflammatory cells and demyelination in peripheral nerves when examined on day 30 after transfer of primed T cells from CD4- 8- mice into identical naive hosts than after transfer of cells from primed wild type, CD4-/- or CD8-/- mice to corresponding recipient animals. EAN in CD4-8- mice was also associated with elevated numbers of P2 peptide-reactive interferon-y (TFN-gamma) secreting cells and alphabeta T cells were present in lymph nodes and spleens. The data suggest that PNS myelin activated T cells from an EAN-resistant mice strain are capable of homing to the PNS. The expanded CD4-8- alphabeta T cells may have helper and effector functions, related to initiation of EAN in the CD4-8- mice. Lack of CD4+ and CD8+ expressing cells does not prevent the initiation of an autoimmune disease.

Animals↗
PubMed1999

Nasal administration of recombinant rat IL-4 ameliorates ongoing experimental autoimmune neuritis and inhibits demyelination.

Experimental autoimmune neuritis (EAN) is a CD4(+)T cell-mediated demyelinating disease of the peripheral nervous system (PNS) and serves as an experimental model for human immune-demyelinating neuropathies. In this study, we examined the effect of recombinant rat interleukin-4 (rrIL-4) on chronic EAN in Lewis rats induced by immunization with P0 peptide 180-199 and complete Freund's adjuvant (CFA). We estimated that nasal administration of rrIL-4, in dose ranges of 0.1-1 microg/rat/day in the initial phase of EAN, decreased the severity and the duration of clinical EAN. Hyporesponsiveness of T cells, downregulation of Th1 cell responses (INF-gamma), but increased levels of specific IgG1 isotypes document that nasal administration of rrIL-4 was systemically immune effective. Low grade inflammation and complete lack of regional demyelination within the sciatic nerves were seen in rrIL-4 treated rats. Based on these observations we suggest that nasal administration of IL-4 could be further evaluated, considering its possible use in human immune-demyelinating neuropathies.

Administration, Intranasal↗
PubMed1999

Autoantibodies against the tumour-associated antigen GA733-2 in patients with colorectal carcinoma.

The tumour-associated antigen (TAA) GA733-2 is expressed as a non-secreted surface molecule on the majority of human colorectal carcinoma cells. The antigen has been used as a target for passive and active immunotherapy during the last decade. To determine the incidence of autoantibodies against this antigen, sera from 1068 patients with colorectal carcinoma were analysed for naturally occurring IgG antibodies against the baculovirus-produced GA733-2E protein. A total of 14.5% of the patients had IgG antibodies against the antigen. In 519 patients, sera were collected at the time of diagnosis and 15% of those patients had anti-GA733-2E IgG antibodies. There was a tendency to a higher frequency of patients with antibodies among those in the advanced Dukes stages: 11% in stage A and 32% in stage D respectively (P = 0.06). Antibodies could be detected for up to 10 years after the diagnosis. Patients with Crohn's disease or colitis ulcerosa (n = 20) did not elicit anti-GA733-2E antibodies. No healthy control donor (n = 45) had detectable antibodies against the antigen. The specificity of GA733-2E-reactive serum IgG was indicated by significant inhibition of mAb17-1A (originally used to define GA733-2) binding to the GA733-2E antigen. Sera of positive patients bound to the GA733-2-expressing human colorectal carcinoma cell line, SW948. No significant correlation was found between the presence of antibodies and survival in the present patient population. However, the high incidence of autoantibodies against this tumour antigen in colorectal carcinoma patients confirms its antigenicity in humans and supports the use of the GA733-2 antigen as a target for immunotherapy.

Adult↗
PubMed1999

A 3-year prospective study on serum tumor markers used for detecting cholangiocarcinoma in patients with primary sclerosing cholangitis.

BACKGROUND/AIMS: Patients with primary sclerosing cholangitis (PSC) have an increased risk of developing cholangiocarcinoma (CC), which is notoriously difficult to diagnose since these patients may have increased levels of bilirubin due to benign strictures. To evaluate the validity of different tumor markers as an aid to diagnosing CC, we have carried out serial serum tumor marker analyses in patients with PSC who have been followed for several years. METHODS: Seventy-five patients with PSC, without any clinical signs of CC were included in the study. They were investigated every 6th months for 3 years, with extensive liver function tests and four tumor serum markers CEA, CA 19-9, CA 50 and CA 242. The patients were then followed for 5 years to exclude the possibility that CC remained unrecognized. RESULTS: Of the 75 patients, two (3%) developed CC during the 3-year period. One of these had normal levels, and one had significantly increased levels of the tumor markers. In the follow-up part of the study two further patients died from CC and one from hepatocellular carcinoma, 3 and 4 years after the 3-year study, respectively. Twenty-one patients had an increase of one of the markers on at least one occasion. Five patients had a transient increase of more than double the upper normal limit of the tumor markers on more than one occasion. There was a good correlation between CA 19-9, CA 50 and CA 242, but not with CEA. Fourteen of the 75 patients had periods of increased bilirubin levels, but none of these showed increased tumor markers. CONCLUSIONS: The serum tumor markers CEA, CA 19-9, CA 50 and CA 242 are of limited value for the detection of CC in patients with PSC because of low specificity. However, we found no falsely increased values in patients with hyperbilirubinemia.

Adult↗
PubMed1999

The role of B-cells in experimental myasthenia gravis in mice.

Myasthenia gravis (MG) and experimental autoimmune myasthenia gravis (EAMG) are caused by auto-antibodies against the nicotinic acetylcholine receptor (AChR) at the postsynaptic membrane. To evaluate the extent to which the humoral immune response against AChR operates in the pathogenesis of EAMG, we immunized B-cell knockout (microMT) and wild type C57BL/6 mice with AChR in complete Freund's adjuvant. The ability of AChR-primed lymph node cells to proliferate and secrete IFN-gamma in response to AChR and its dominant peptide alpha 146-162 were intact in microMT as in wild type mice. Similar levels of mRNA for IFN-gamma, IL-4 and IL-10 in AChR-reactive lymph node cells were detected in microMT and wild type mice. However, microMT mice had no detectable anti-AChR antibodies and never developed clinical EAMG. We conclude that B-cells are critically required for the genesis of clinical EAMG, but not for AChR-specific T-cell priming.

Animals↗
PubMed1999

Prevalence of herpes simplex virus types 1 and 2, cytomegalovirus, and varicella-zoster virus infections in Eritrea.

BACKGROUND: Herpesviruses establish latent infections in their hosts for life. The scarcity of data that exists in regard to herpesvirus infections in many African regions, could partly be due to the mild nature of their primary infections and the lack of means for their proper diagnosis. However, in recent decades the alarming spread of HIV infection in Africa and associated frequent reactivation of herpesvirus infections is leaving less room for neglect. This seroprevalence study is intended to help in the evaluation of the prevalence of herpesvirus infections in Eritrea. OBJECTIVE: To evaluate the spread of herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), cytomegalovirus (CMV), and varicella-zoster virus (VZV) infections. STUDY DESIGN: The study population groups comprise female sex workers (FSW), former guerrilla fighters, truck drivers, port workers, a tribe called Rashaida, pregnant women, children under 5 years of age, and children over 5 years of age. The groups of pregnant women and children under and over 5 years of age were included to form a background for the evaluation of groups considered at risk for sexually transmitted or blood borne infections. RESULTS: All study groups had a high seroprevalence of HSV-1 infections ( > 80%), except for the children under 5 years of age. The FSW had the highest prevalence of HSV-2 infections, 80%, followed by guerrilla fighters, truck drivers, port workers, pregnant women, children, and the Rashaidas. Positivity for antibodies against CMV was > 90% in all studied populations. The prevalence of VZV infections was surprisingly low in the tribe of Rashaida, 44% compared to more than 90% in the other adult groups tested for VZV (P = 0.0001). CONCLUSION: The study shows that the prevalence of HSV-2 in the risk group of FSW was high, which could partly be explained by their sexual behaviours. HSV-2 was particularly low in the Rashaida group and, as expected, in the children. The low prevalence of VZV observed in the Rashaida is of importance since it makes them vulnerable to infection with varicella during their inevitable integration with the other tribes in their society.

Adult↗