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Biomedical subjects

G Lack

Publications and source records attributed to G Lack.

At least 19 recordsLinked to original sources
PubMed2001

Pediatric allergic rhinitis and comorbid disorders.

Allergic rhinitis (AR) is rarely found in isolation and needs to be considered in the context of systemic allergic disease associated with numerous comorbid disorders, including asthma, chronic middle ear effusions, sinusitis, lymphoid hypertrophy with obstructive sleep apnea, disordered sleep, and consequent behavioral and educational effects. The coexistence of AR and asthma is complex. First, the diagnosis of asthma may be confounded by symptoms of cough caused by rhinitis and postnasal drip. This may lead to either inaccurate diagnosis of asthma or inappropriate assessment of asthma severity with over treatment of the patient. The term "cough variant rhinitis" is therefore proposed to describe rhinitis that manifests itself primarily as cough that results from postnasal drip. AR, however, also has a causal role in asthma; it appears both to be responsible for exacerbating asthma and to have a role in its pathogenesis. Postnasal drip with nasopharyngeal inflammation leads to a number of other conditions. Thus sinusitis is a frequent extension of rhinitis and is one of the most frequently missed diagnoses in children. Allergen exposure in the nasopharynx with release of histamine and other mediators can cause Eustachian tube obstruction possibly leading to middle ear effusions. Chronic allergic inflammation of the upper airway causes lymphoid hypertrophy with prominence of adenoidal and tonsillar tissue. This may be associated with poor appetite, poor growth, and obstructive sleep apnea. AR is therefore part of a spectrum of allergic disorders that can profoundly affect the well being and quality of life of a child. Prospective cohort studies are required to assess the disease burden caused by AR in childhood and to further assess the potential educational impairment that may result. Because AR is part of a systemic disease process, its management requires a coordinated approach rather than a fragmented, organ-based approach.

Asthma↗
PubMed1998

Peanut allergy.

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Arachis↗
PubMed1997

Posttranscriptional regulation of T-cell IL-2 production by human pooled immunoglobin.

We evaluated the mechanism by which human pooled gamma-globulin for intravenous use (hIVIG) inhibits interleukin-2 (IL-2) production by human T cells. hIVIG reduced by 70-95% the amount of IL-2 in culture supernatants from mitogen-stimulated peripheral blood T cells or Jurkat cells. This reduction was not apparent at the transcriptional level: hIVIG had no effect on the levels of IL-2 mRNA or on the accumulation of firefly luciferase when its gene was linked to the IL-2 promoters. In contrast, hIVIG inhibited IL-2 protein synthesis, and the intracellular IL-2 was not restored by monensin. Our results indicate that the inhibition of IL-2 production by hIVIG occurred post-transcriptionally, and also suggest that secretion was unaffected, and that this effect of hIVIG was specific for IL-2 (and possibly other related cytokines). The data identify a previously uncharacterized regulatory mechanism of IL-2 production and predict that this immunomodulatory effect of hIVIG may be significant for its therapeutic actions in immune-mediated diseases.

Adult↗
PubMed1997

Rush immunotherapy results in allergen-specific alterations in lymphocyte function and interferon-gamma production in CD4+ T cells.

BACKGROUND: Allergen immunotherapy results in a number of changes in clinical, inflammatory, and immunologic parameters. However, the basis for the specificity of this form of therapy is unknown, especially in the context of changes in T- and B-lymphocyte function after desensitization to specific allergens. OBJECTIVE: This study was designed to determine the immunologic consequences of rush immunotherapy. METHODS: We studied 10 patients who had positive skin test responses to the house dust mite Dermatophagoides pteronyssinus (Dpt) and cat dander extract. Each received rush immunotherapy to mite, but not cat dander, over a 2- to 4-week period until maintenance was achieved. Patients were evaluated before and when maintenance was achieved for skin test and nasal reactivity to mite and cat dander; antibody levels to the allergen were monitored, as were lymphocyte proliferative responses and cytokine production. RESULTS: Rush immunotherapy to house dust mite resulted in a significant reduction in skin and nasal reactivity to mite allergen, but not to cat allergen, in 10 of 10 patients. This was accompanied by a rise in serum anti-Dpt IgE, whereas anti-cat IgE was not altered (7 of 7 patients). In seven of seven patients there was an increase in anti-Dpt IgG4 levels. T-cell proliferative responses to mite antigen were suppressed, and numbers of CD8+ T cells increased in frequency. There was a marked increase in interferon-gamma production, particularly by CD4+ T cells in 10 of 10 patients. The correlation between the increases in interferon-gamma production and the changes in cutaneous reactivity was highly significant. CONCLUSION: We show that rush immunotherapy is immunologically specific in eliciting changes in T- and B-cell responses to the desensitization antigen. The specificity and potential benefit of immunotherapy may be linked to the increase in interferon-gamma production by allergen-activated CD4+ T lymphocytes.

Adolescent↗
PubMed1996

Nebulized IFN-gamma inhibits the development of secondary allergic responses in mice.

The effects of nebulized IFN-gamma on primary and secondary IgE production and development of airway hyper-responsiveness (AHR) were investigated. BALB/c mice received primary exposure to aerosolized OVA daily for 10 days and developed anti-OVA IgE responses, immediate cutaneous reactivity to OVA, and altered airway function when assayed on day 12. After secondary exposure to OVA challenges on days 30 and 31, these mice developed an amplified IgE response, heightened cutaneous reactivity to OVA and AHR when measured on day 37. Administration of IFN-gamma for 13 days, beginning 3 days prior to and during primary OVA sensitization, resulted in a decrease in anti-OVA IgE, increases in serum anti-OVA IgG2a levels, a decrease in cutaneous reactivity to OVA, and normal airway function when assessed on day 12 after primary sensitization. This treatment also prevented the development of secondary anti-OVA IgE responses and altered airway responsiveness but did not induce a secondary rise in anti-OVA IgG2a in the serum measured on day 37. Treatment with IFN-gamma on days 26 to 30, well after primary responses were established but just prior to secondary OVA challenge, abolished the development of secondary anti-OVA IgE responses, resulted in an increase in anti-OVA IgG2a in the serum, and prevented the development of AHR. In vitro, CD4+ T cells obtained from OVA-sensitized mice treated with either "early" or "late" IFN-gamma inhibited IgE production. Delivery of IFN-gamma to the airways can prevent secondary allergen sensitization even after primary sensitization has been achieved and this effect is mediated by CD4+ T cells.

Administration, Inhalation↗
PubMed1996

Triggering through CD40 promotes interleukin-4-induced CD23 production and enhanced soluble CD23 release in atopic disease.

The pathogenesis of atopic disease is closely linked to the overproduction of IgE. CD23 and CD40 are two cellular receptors involved in the regulation of IgE production and both receptors are elevated in atopic disease. We have examined the role of CD40 in the regulation of CD23 and soluble CD23 production in healthy and atopic donors. Triggering of the B cell CD40 receptor directly enhances interleukin (IL)-4-mediated up-regulation of CD23 at both the protein and the mRNA level. When atopic donors were studied, the synergistic effect of CD40 triggering on the IL-4-induced up-regulation of CD23 and soluble CD23 (sCD23) was enhanced and there was a relative skewing toward production of sCD23. These studies implicate the CD40 receptor in the hyperproduction of CD23 and sCD23 in atopic disease and suggest that abnormalities may exist in the cellular pathways leading to sCD23 production.

Antibodies, Monoclonal↗
PubMed1996

Humoral immunity in steroid-dependent children with asthma and hypogammaglobulinemia.

OBJECTIVE: To determine primary and secondary antibody responses in children with hypogammaglobulinemia attributed to corticosteroid use. RESULTS: In seven patients with steroid-dependent asthma and significant hypogammaglobulinemia (IgG concentration, 275 to 443 mg/dl), antibody responses to protein and polysaccharide antigens were shown to be normal, as were primary and secondary responses to a neoantigen, bacteriophage phi X174. CONCLUSIONS: Patients with asthma, and with hypogammaglobulinemia resulting from steroid therapy, have normal humoral immunity, and immunoglobulin replacement therapy is not indicated.

Adolescent↗
PubMed1995

Modification of immediate hypersensitivity responses by staphylococcal enterotoxin B.

The staphylococcal enterotoxins have been termed superantigens based on their ability to stimulate polyclonal proliferative responses of murine and human T lymphocytes expressing particular T-cell receptor V beta gene products. Certain of these toxins have been shown both to activate and to induce anergy in reactive T cells. Staphylococcal enterotoxin B is known to interact with murine T cells bearing V beta 3, -7, -8.1, -8.2, -8.3, and -17. In BALB/c mice V beta 3+ and V beta 17+ T cells are deleted; V beta 7+ T cells are low in frequency. BALB/c mice sensitized to ovalbumin via the skin and airways develop immediate hypersensitivity including IgE/IgG1 antiovalbumin antibodies, immediate cutaneous reactivity to ovalbumin and, increased airway responsiveness. In both in vitro and in vivo studies, the development of these responses has been associated with the V beta 8+ subset of T cells and controlled by V beta 2 + T cells. In view of the central role of V beta 8+ T cells in these responses, we tested the effects of staphylococcal enterotoxin B on the development of immediate hypersensitivity in this system. Intradermal injection of staphylococcal enterotoxin B prevented the development of these responses in the absence of a major deletion of V beta 8+ T cells. The data suggest that the administration of staphylococcal enterotoxin B prevented the antigen-induced expansion of V beta 8+ T cells resulting in a state of responsiveness or anergy, thus preventing the manifestations of immediate hypersensitivity. Bacterial toxins may provide a novel approach to intervention in allergic or autoimmune diseases.

Allergens↗
PubMed1995

Decreased frequency of interferon-gamma- and interleukin-2-producing cells in patients with atopic diseases measured at the single cell level.

BACKGROUND: Recently, diminished interferon-gamma (IFN-gamma) and increased interleukin (IL-4 production in peripheral blood mononuclear cells (PBMCs) from atopic patients have been described by several groups, measured as total cytokine content in culture supernatants. These studies suggested a predominance of TH2-like cells producing large amounts of IL-4 in atopic patients. It is not clear whether the reported cytokine imbalances are the result of an alteration in the distribution of specific T-cell subsets or whether intrinsic dysregulation in cytokine production is a characteristic of atopic individuals. OBJECTIVE: This study examined the production of IFN-gamma, and IL-2 in PBMCs from atopic patients at the single cell level with the use of freshly isolated lymphocytes. METHODS: We recently described a flow cytometric assay in which three-color analysis was used to study the production of a cytokine of interest in a T-cell subpopulation defined by two cell surface markers. PBMCs from 23 atopic patients and 14 control subjects were stimulated with phorbol ester and ionomycin for 5 hours. PBMCs from seven patients and seven control subjects were also cultured with immobilized anti-CD3 antibodies for 24 hours. Cells were fixed, made permeable, and stained for intracellular cytokines in combination with cell surface markers CD3, CD8, and CD45RO. Cytokine-producing cells were analyzed by gating on T-cell subsets. RESULTS: IFN-gamma-producing cells were significantly decreased (p < 0.05) in CD4+ T cells but not in CD8+ T cells of atopic patients. CD45R0+ and CD45R0-T cells showed a decreased proportion of IFN-gamma-producing cells (p < 0.05 and p < 0.01, respectively). IL-2 production was diminished in all T-cell subsets (p < 0.01). The number of IL-4-producing cells was not elevated, and such cells were exclusively found in the CD45RO+ T cells. Analysis of culture supernatants of sorted CD45RO+ T cells for IL-4 and IFN-gamma production confirmed these results. CONCLUSION: Our findings provide evidence that a reduced IFN-gamma production in atopic patients is due to an intrinsic defect selectively found in the CD4+ T cells. Because IL-2 production was markedly decreased but IL-4 production was unchanged, our data demonstrate a deficiency in the ability of atopic T cells to produce TH1-like cytokines on stimulation with phorbol ester, ionomycin, or anti-CD3 monoclonal antibodies.

Adolescent↗
PubMed1995

Transfer of immediate hypersensitivity and airway hyperresponsiveness by IgE-positive B cells.

The role of allergen-specific sIgE+ B cells in the development of airway hyperresponsiveness to electrical field stimulation was examined in a murine model of allergic sensitization. Ovalbumin (OVA)-specific B cells (OVA+) were isolated from mice that were sensitized to aerosolized OVA. The OVA+ B cell population was shown to be distinct from the remaining, non-OVA-responsive B cells (OVA-). There was a high frequency of sIgE+ B cells and a low frequency of sIgG+ B cells in the OVA+ population compared with the OVA- population, where the ratio was reversed. Although both populations produced immunoglobulin in vitro, only the OVA+ cells secreted anti-OVA antibodies. Transfer of 10(6) OVA+ B cells or as few as 5 x 10(4) OVA+/sIgE+ B cells was able to transfer the capability for anti-OVA IgE synthesis and cutaneous reactivity to OVA in naive recipients. Exposure to OVA via the airways in addition to transfer of OVA+ B cells was necessary for development of airway hyperresponsiveness, whereas recipients challenged with an irrelevant allergen, ragweed, had normal airway function. Transfer of up to 10(7) OVA- B cells failed to induce production of anti-OVA IgE. Despite production of polyclonal IgE, recipients of OVA- B cells did not develop airway hyperresponsiveness after OVA challenge. We conclude that both allergen-specific IgE production and local challenge via the airways with specific allergen are necessary to change airway function in this model.

Animals↗