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Allergy consists of a group of heterogeneous diseases with different underlying mechanisms. However, common allergies including eczema, hay fever, and allergic asthma, characterized by immediate hypersensitivity reactions, are mediated by IgE, which is produced and regulated by the B cells as well as T helper type 2 (Th2) and type 17 (Th17) cells (1–3). Allergic symptoms result from cross-linking of IgE to an allergen on the surface of mast cells, leading to the release of granules including histamine and other inflammatory substances. Two broad classes of IgE participate in the allergic response, allergen-specific IgE, which recognizes specific components of an allergen, and total IgE, which recognizes these components and, in addition, includes antibodies of unknown specificity and function (4). Levels of allergen-specific IgE are used, together with allergic symptoms, to diagnose allergies. However, there are allergies, such as contact allergies, that do not involve IgE (5), and conversely, elevated levels of either allergen-specific or total IgE are not necessarily associated with allergic symptoms (6,7). Many observational studies have been conducted to determine whether having a history of allergy is associated with a reduced risk of cancer (8,9). Findings from most of these studies are conflicting, with varying results both within and among cancer sites. In contrast, the inverse association between self-reported allergy and glioma has been consistently observed in case–control studies (10–12). In addition, there are two recent nested case–control studies (13,14), in which prediagnostic IgE concentration was used as a biomarker of allergy. In the first study, Schlehofer et al. (13) found an association between those testing positive for respiratory allergen-specific IgE (>0.35 kUA/L) and decreased risk of glioma compared with those testing negative (≤0.35 kUA/L) (odds ratio [OR] = 0.73, 95% confidence interval [CI] = 0.51 to 1.06). In contrast, Calboli et al. (14) found no association between prediagnostic respiratory allergen-specific IgE levels and risk of glioma. However, they reported an association between borderline elevated total IgE levels (25–100 kU/L) and decreased risk of glioma compared with normal levels ( 100 kU/L) compared with normal levels (14). Glioma consists of morphologically heterogeneous tumors reflecting germline genetic variation and possibly differences in etiology (15), and the most common glioma subtype is glioblastoma. Schlehofer et al. (13) found that the association between testing positive for respiratory allergen-specific IgE and high-grade (grade 3 [anaplastic astrocytoma] and grade 4 [glioblastoma]) glioma (a category that consists of both anaplastic astrocytoma and glioblastoma) was stronger than the association between testing positive for allergen-specific IgE and all grades of glioma combined. Although Calboli et al. (14) reported that stratifying on glioblastoma did not substantially alter their results, their sample was small (n = 103 glioblastoma case subjects), making this finding difficult to interpret. In this study, we aimed to further determine the degree to which respiratory allergen-specific or total IgE levels are associated with the risk of glioma or glioblastoma. We conducted a nested case–control study using prospectively collected stored serum samples from the Janus Serum Bank (Oslo, Norway).

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.

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.