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D Broide

Publications and source records attributed to D Broide.

14 recordsLinked to original sources
PubMed2001

DNA-based immunotherapeutics for the treatment of allergic disease.

Allergic diseases are a growing health concern in industrialized countries. Despite a number of effective therapeutic options for the prevention and treatment of the pathophysiologic responses which characterize allergic diseases, the induction of true allergen desensitization remains an elusive therapeutic goal. Only immunotherapy (IT) has been shown to have any effect on the underlying hypersensitivities which mediate allergic reactions, and traditional protein-based allergen IT has a limited scope of efficacy However, a number of reagents collectively termed DNA-based immunotherapeutics have proven highly effective in both the prevention and reversal of Th2-mediated hypersensitivity states in mouse models of allergic disease. Four basic DNA-based immunotherapeutic modalities have been used for these studies. These include immunization with gene vaccines, allergen mixed with immunostimulatory oligodeoxynucleotide (ISS-ODN), and physical allergen-ISS-ODN conjugates (AIC), as well as immunomodulation with ISS-ODN alone. Results from many laboratories have generated guarded optimism that DNA-based immunotherapeutics may be effective for the reversal of allergic hypersensitivity states in humans, and several clinical trials have already been initiated. This review will focus on our present understanding of the biological activities of DNA-based immunotherapeutics and their application to the treatment of allergic diseases.

Adjuvants, Immunologic↗
PubMed2001

Eosinophil trafficking to sites of allergic inflammation.

Eosinophils play a prominent pro-inflammatory role in allergic inflammation. Studies utilizing flow chambers, intravital video-microscopy, and cytokine and adhesion molecule-deficient mice have provided important insight into the mechanisms of eosinophil trafficking in inflamed blood vessels and into tissues in vivo. While the bone marrow generation of eosinophils is finely regulated by interleukin (IL)-5, the trafficking of eosinophils into tissues is regulated by several cytokines, chemokines, and adhesion molecules with overlapping functions. Prospects for therapeutically inhibiting eosinophilic inflammation by inhibiting eosinophil adhesion to endothelium are dependent on an improved understanding of the relative importance of individual cytokines and adhesion molecules in regulating eosinophil adhesion to endothelium. Alternative strategies to inhibit eosinophilic inflammation include the use of immunostimulatory DNA sequences containing a CpG motif to act as a Th1 adjuvant to prevent Th2 responses associated with IL-5 and eosinophilia. Immunostimulatory DNA sequences do not induce eosinophil apoptosis, but function at the level of the bone marrow to inhibit the IL-5-induced bone marrow generation and release of eosinophils.

Adjuvants, Immunologic↗
PubMed1999

Inhibition of allergic inflammation in the lung by plasmid DNA allergen immunization.

The nature of the immune response (Th1/Th2) in mice to protein antigens or allergens was compared to that of immunization with pDNA encoding the same antigens. pDNA immunization induced a Th1 response and no IgE antibodies whereas the proteins induced a Th2 response and IgE antibodies. Furthermore, the pDNA induced Th1 response dominated over the protein elicited Th2 response in a secondary immune response. In particular, a preexisting Th2 response (as is the case in allergic patients) did not prevent a new Th1 response to an allergen-pDNA booster injection. The major reason why pDNA immunization induced a Th1 response to allergens was the presence of immunostimulatory non-coding DNA sequences (ISS) in the plasmid constructs having a CpG motif. These ISS caused antigen presenting cells to secrete INF-alpha, INF-beta and IL-12, all cytokines that induce naive T cells to differentiate into CD4+ Th1 cells and CD8+ Tc1 cells. Passive transfer of both Th1 and Tc1 cells from pDNA immunized mice into naive mice inhibited a Th2 response and IgE antibody formation to a subsequent injection of allergen in alum. pDNA immunization or ISS-oligonucleotide injection prior to allergen challenge reduced both immediate type airway sensitivity and late phase allergen induced eosinophil filtration of the lung. Allergen-pDNA immunization may provide a novel type of immunotherapy for the treatment of allergic diseases in man. Since only small amounts of allergen are secreted by the allergen-pDNA transformed cells, allergen-pDNA immunotherapy will unlikely carry the risk of the anaphylactic reactions that are associated with classical allergen injection immunotherapy.

Allergens↗
PubMed1998

Immunostimulatory DNA sequences inhibit IL-5, eosinophilic inflammation, and airway hyperresponsiveness in mice.

We have used a mouse model of allergen-induced airway hyperresponsiveness to demonstrate that immunostimulatory DNA sequences (ISS) containing a CpG DNA motif significantly inhibit airway eosinophilia and reduce responsiveness to inhaled methacholine. ISS not only inhibited eosinophilia of the airway (by 93%) and lung parenchyma (91%), but also significantly inhibited blood eosinophilia (86%), suggesting that ISS was exerting a significant effect on the bone marrow production of eosinophils. The inhibition of the bone marrow production of eosinophils by 58% was associated with a significant inhibition of T cell-derived cytokine generation (IL-5, granulocyte-macrophage CSF, and IL-3). ISS exerted this inhibitory effect on T cell cytokine production indirectly by stimulating monocytes/macrophages and NK cells to generate IL-12 and IFNs. The onset of the ISS effect on reducing the number of tissue eosinophils was both immediate (within 1 day of administration) and sustained (lasted 6 days), and was not due to ISS directly inducing eosinophil apoptosis. ISS was effective in inhibiting eosinophilic airway inflammation when administered either systemically (i.p.), or mucosally (i.e., intranasally or intratracheally). Interestingly, a single dose of ISS inhibited airway eosinophilia as effectively as daily injections of corticosteroids for 7 days. Moreover, while both ISS and corticosteroids inhibited IL-5 generation, only ISS was able to induce allergen-specific IFN-gamma production and redirect the immune system toward a Th1 response. Thus, systemic or mucosal administration of ISS before allergen exposure could provide a novel form of active immunotherapy in allergic diseases.

Adjuvants, Immunologic↗
PubMed1998

Immunostimulatory DNA is a potent mucosal adjuvant.

Most proteins delivered to mucosal surfaces fail to induce mucosal or systemic immune responses. We demonstrate that a single intranasal (i.n.) coadministration of a model antigen (beta-galactosidase, beta-gal) with immunostimulatory sequence oligodeoxynucleotide (ISS-ODN) induces a mucosal IgA response equivalent to that induced by i.n. codelivery of beta-gal with cholera toxin (CT). Furthermore, i.n. and intradermal (i.d.) delivery of the beta-gal/ISS-ODN mix stimulates equivalent Th1-biased systemic immune responses with high-level cytotoxic T lymphocyte (CTL) activity. In contrast, i.n. immunization with beta-gal and CT results in a Th2-biased systemic immune response with poor CTL activity. Our data show that i.n. delivery of ISS-ODN provides effective adjuvant activity for the induction of both mucosal and systemic Th1-biased immune responses. This immunization approach deserves consideration in the development of vaccines against mucosal pathogens.

Adjuvants, Immunologic↗
PubMed1998

DNA immunotherapeutics: new potential treatment modalities for allergic disease.

Genetic immunization is a relatively new approach to vaccination, one that has generated considerable interest for its potential to prevent or treat a number of types of disease processes. Although initial work focused on potential applications in infectious disease, it was soon recognized that the antigen-specific Th1 response typically generated by genetic immunization protocols could also be useful for the treatment of allergic disease. In this review we present a summary of genetic vaccination and the related topic of immunostimulatory DNA sequences - which we collectively designate DNA immunotherapeutics - and discuss their potential for the prevention and therapy of allergic disease.

Animals↗
PubMed1988

Cytokines in chronic inflammatory arthritis. I. Failure to detect T cell lymphokines (interleukin 2 and interleukin 3) and presence of macrophage colony-stimulating factor (CSF-1) and a novel mast cell growth factor in rheumatoid synovitis.

Because previous studies showed low levels of IFN-gamma in rheumatoid arthritis (RA) synovial fluid (SF) and synovial tissue (ST) explant supernatants, we assayed RA SF and ST for IL-2 and IL-3-like activity. Using an IL-2 dependent murine CTLL line, 6 of 14 RA SF caused increased thymidine uptake (greater than three times control). The activity was distinct from IL-2 because it was not blocked by antibody to IL-2-R. In addition, IL-2 was not detected (less than 50 pg/ml) in 16 joint samples using an ELISA. Multi-colony-stimulating factor (CSF) activity was measured using two assays that can detect murine IL-3 (mast cell proliferation, and bone marrow CSF). In the mast cell assay, [3H]TdR uptake was 493 +/- 67 cpm for medium, 2,910 +/- 329 cpm in the presence of RA SF (p less than 0.001), 1,246 +/- 156 cpm in the presence of SF from patients with seronegative spondyloarthropathies (p less than 0.001), and 736 +/- 100 cpm in the presence of osteoarthritis SF (p greater than 0.1). In the CSF assay, four of five RA SF and five of five RA ST induced colony formation from bone marrow nonadherent cells. Macrophage colonies were most common, although mixed colonies and granulocytes were occasionally observed. The multi-CSF activity in RA is not due to IL-3 since human rIL-3 was not active in either murine assay, and IL-3 mRNA was not detected in RA synovium. Sephadex column chromatography of RA SF revealed that the mast cell growth factor (approximately 6 x 10(3) mol wt) and the CSF (approximately 40 and 100 x 10(3) mol wt) are distinct. The colony-stimulating aspect of the "IL-3-like" activity in RA SF is likely due to CSF-1 because it is the appropriate mol wt and because the activity was neutralized by specific anti-CSF-1 antibody. Finally, an RIA detected 1.6-25 ng/ml of CSF-1 in RA SF and ST and CSF-1 mRNA was detected in four of five RA synovial tissue samples tested.

Arthritis, Rheumatoid↗
PubMedDate not supplied

DNA-Based immunization for asthma.

BACKGROUND: Immunostimulatory DNA sequences (ISS) containing a CpG motif are able to inhibit Th2-mediated airway eosinophilia and bronchial hyperresponsiveness in a mouse model of asthma. METHODS: To determine the optimal frequency and timing of intervention with ISS in inhibiting Th2 cytokine production and airway eosinophilia, we used ISS administration protocols which differed in the frequency (one vs. two doses), route (systemic vs. mucosal) and timing of ISS administration (before or together with antigen) in a mouse model of ovalbumin-induced eosinophilic airway inflammation. RESULTS: ISS induced Th1 cytokine production (IFN-gamma) and effectively inhibited Th2 cytokine production (IL-5) as well as eosinophilic inflammation when ISS was administered before or coadministered with inhaled allergen challenge. Although ISS was effective when coadministered with inhaled allergen, it was most effective when administered once 6 days prior to allergen challenge. Mucosal (intranasal and intratracheal) delivery of ISS was as effective as systemic (intraperitoneal) ISS delivery in inhibiting airway eosinophilia and switching cytokine responses from a Th2 to a Th1 response. CONCLUSIONS: ISS is most effective in inhibiting airway eosinophilia when administered as a single dose 6 days prior to antigen inhalation. However, ISS can also significantly inhibit eosinophilic inflammation, when coadministered with antigen inhalation. Thus, ISS administered prior or together with allergen should be considered as a novel method of allergen-based immunotherapy.

Allergens↗