BackgroundPrevious nested case–control studies suggest that a prediagnostic biomarker of allergy, IgE, is inversely associated with the risk of glioma, but these findings are inconsistent. The purpose of our study was to assess this association and determine how long before glioma diagnosis it may be observed. MethodsWe conducted a nested case–control study using serum specimens from the Janus Serum Bank cohort in Norway. Blood donors who were subsequently diagnosed with glioma (n = 594 case subjects), between January 1, 1974 to December 31, 2007, were matched with subjects without glioma (n = 1177 control subjects) for date of blood collection, 2-year age interval at blood collection, and sex. Respiratory allergen-specific and total IgE levels in the serum were measured using fluorescent assays. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression models stratified on sex and glioblastoma, the most common glioma subtype. Data were stratified on time from blood collection to tumor diagnosis to assess how long before glioma diagnosis the association could be observed. ResultsAmong women, testing positive for allergen-specific IgE (>0.35 kUA/L) was associated with decreased risk of glioblastoma compared with testing negative (≤0.35 kUA/L; OR = 0.46, 95% CI = 0.23 to 0.93). Among both sexes combined, testing positive for total IgE (>100 kU/L) was associated with decreased risk of glioma compared with testing negative (≤100 kU/L; OR = 0.75, 95% CI = 0.56 to 0.99), and simultaneously testing positive for allergen-specific IgE and total IgE was associated with a borderline statistically significantly decreased risk of glioblastoma and glioma compared with simultaneously testing negative for these types of IgE. Testing positive for total IgE at least 20 years before diagnosis was associated with decreased risk of glioma compared with testing negative (OR = 0.54, 95% CI = 0.30 to 0.99). ConclusionAn inverse association between IgE levels and risk of glioma was detected; the association was present at least 20 years before tumor diagnosis.
While monoclonal antibodies show promise for use in the treatment of a variety of disease states, including cancer, autoimmune disease, and allograft rejection, generation of anti-antibody responses still remains a problem. For example, 50% of the patients who receive OKT3 produce blocking antibodies that interfere with its binding to T cells, thus decreasing the therapeutic effect (51). HAMA responses have also interfered with tumor imaging (39,40) and radioimmunotherapy (56). The generation of an anti-antibody response is dependent on many factors. These include the dose of antibody, the number of injections of antibody, the immunogenicity of the antibody, the form of the antibody, and the immunocompetence of the recipient. Predictably, both the number of injections of antibody and the dosage are influential in the generation of an anti-antibody response. It is apparent that human antibodies, chimeric antibodies, and mouse Fab fragments are much less likely to induce anti-antibody responses than intact mouse monoclonal antibodies or mouse F(ab')2 fragments when one injection is administered. Injections of human or chimeric antibodies appears to reduce immunogenicity, but the probability that anti-antibody responses can still be induced on multiple injections must be considered and appropriately evaluated. Several areas demand extensive investigation to enhance the clinical utility of monoclonal antibodies. First, results of thorough clinical trials with human or chimeric antibodies need to be evaluated for the induction of anti-antibodies after multiple injections of antibodies. Second, less immunogenic forms of antibodies (Fab, Fv) need to be studied for their clinical efficacies and for their abilities to induce anti-antibody responses.
Previously we reported the development of a plasmid DNA expression vector system derived from Sindbis virus (T. W. Dubensky, Jr., et al., J. Virol. 70:508–519, 1996). In vitro, such vectors exhibit high-level heterologous gene expression via self-amplifying cytoplasmic RNA replication. In the present study, we demonstrated the in vivo efficacy of the Sindbis virus-based pSIN vectors as DNA vaccines. A single intramuscular immunization of BALB/c mice with pSIN vectors expressing the glycoprotein B of herpes simplex virus type 1 induced a broad spectrum of immune responses, including virus-specific antibodies, cytotoxic T cells, and protection from lethal virus challenge in two different murine models. In addition, dosing studies demonstrated that the pSIN vectors were superior to a conventional plasmid DNA vector in the induction of all immune parameters tested. In general, 100- to 1,000-fold-lower doses of pSIN were needed to induce the same level of responsiveness as that achieved with the conventional plasmid DNA vector. In some instances, significant immune responses were induced with a single dose of pSIN as low as 10 ng/mouse. These results indicate the potential usefulness of alphavirus-based vectors for DNA immunization in general and more specifically as a herpes simplex virus vaccine.
We have studied parameters affecting in vivo expression of human growth hormone (hGH) in mice after intravenous administration of a retroviral vector encoding the protein as a model system for clotting factor VIII gene therapy. Such treatment results in a brief burst of high-level expression followed by lower level sustained expression of the hGH in the circulation. The major targets for transduction in the mouse are liver and spleen. Such direct transduction (i.e., without surgical or chemical induction of cell division) requires vector at high titer (>/=10(8) cfu/ml) and is dose dependent. Transduction efficiency decreases with increasing age of the recipient. Nevertheless, long-term expression in adults is observed after administration of vector as a split dose on 2 consecutive days. We also show that anti-vector immune responses may enhance long-term expression and that both anti-vector and anti-transgene immunity can be modulated. This work provides a framework for the rational development of means to enhance the efficiency of retroviral vectors for use in clinical gene replacement therapy.
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