The role of nebulized IFN-gamma in the modulation of allergic responses.
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Allergens↗
Biomedical subjects
G Lack
Publications and source records attributed to G Lack.
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↗
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↗
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↗
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↗
Therapeutic interference with interferon-gamma (IFN-gamma) and soluble IL-4 receptor (sIL-4R) in allergic diseases.
Allergic sensitization is controlled by CD4+ T cells. A complex interaction between antigen-presenting cells, T- and B-cells results in the production of (allergen) specific IgE. Analysis of the lymphokine profile of lymphocytes from patients with bronchialasthma and atopic dermatitis revealed an imbalance in cytokine production. An enhanced production of IL-4 was accompanied by low or absent amounts of IFN-gamma. Since both cytokines play a central role in the regulation of IgE, it was examined whether therapeutic interference on the level of cytokine production may provide an useful tool to alter lymphocyte functions in allergic diseases. Two different model systems were employed to study the effects of soluble IL-4R (sIL-4R) under in vitro and in vivo conditions. (1) A mouse model system for allergic sensitization and increased airways responsiveness (AR) was employed to examine whether in vivo treatment with recombinant murine sIL-4R may prevent the development of allergic sensitization. It was found that local treatment through the airways and the lung as carried out by aersolization of the receptor offered a route of application that prevented the development of allergen-induced and allergen-dependent immediate hypersensitivity responses including the development of increased AR. (2). The in vitro effects of humans sIL-4R on functions of mononuclear cells prepared from two patients with most severe atopic dermatitis were examined. Incubation of lymphocytes with allergens in the presence and absence of sIL-4R indicated that the soluble receptor suppressed allergen-induced lymphocyte proliferation and allergen-dependent IgE, IgG and IgM production. In addition a complete suppression of allergen-specific IgE production was detected in the presence of sIL-4R. These data suggest that sIL-4R may provide a useful drug to modify lymphocyte-dependent immune functions in allergic diseases.
Allergens↗
Nebulized but not parenteral IFN-gamma decreases IgE production and normalizes airways function in a murine model of allergen sensitization.
An animal model of local allergen (airways) sensitization was employed to study the effects of rIFN-gamma administered by ultrasonic nebulization through the airways on IgE production and airways responsiveness. BALB/c mice exposed to aerosolized OVA daily for 10 days developed a predominant anti-OVA IgE response, immediate cutaneous reactivity to OVA, and increased airways responsiveness (AR). Mice were treated with rIFN-gamma, either systemically or locally via the airways, following different protocols; i.p. rIFN-gamma failed to modulate the course of OVA sensitization, although total IgE levels in the serum were decreased by 50%. Anti-OVA IgE levels remained elevated, immediate skin test responses to OVA persisted, and AR was increased. However, local treatment of the airways with nebulized rIFN-gamma caused a 66% decrease in serum anti-OVA IgE and a twofold rise in IgG2a levels. Cutaneous reactivity to OVA was reduced and AR was also normalized after nebulized rIFN-gamma. In contrast to the i.p. route, treatment with nebulized rIFN-gamma resulted in a reduction in the in vitro IgE production by lymphocytes in response to OVA and IL-4. The timing of treatment with nebulized rIFN-gamma was important in determining the immunomodulatory response. Treatment after day 7 of OVA exposure failed to modulate sensitization. Treatment regimens with nebulized rIFN-gamma that began before day 7 of OVA exposure were able to decrease anti-OVA IgE. Only treatment regimens that included 3 days of nebulized IFN-gamma before OVA sensitization caused a decrease in cutaneous reactivity and normalization of AR. The data demonstrate that both the route and timing of rIFN-gamma administration are critical factors in the immunomodulation of the immediate allergic response to allergen sensitization via the airways.
Aerosols↗
Inhibition of IgE production and normalization of airways responsiveness by sensitized CD8 T cells in a mouse model of allergen-induced sensitization.
The functional role of CD8 T cells in in vivo IgE production, immediate cutaneous reactivity, and altered airways responsiveness (AR) was examined in a murine model of allergen-induced sensitization. Exposure of BALB/c mice to nebulized OVA triggered an IgE anti-OVA response in the serum, immediate-type skin test responses to OVA, and the development of increased AR (as measured by nonspecific reactivity to electrical field stimulation). In spleens of sensitized mice, analysis of the distribution of CD4/CD8 T cell subpopulations revealed an increase in total numbers of CD8 T cells. Transfer of purified spleen CD8 T cells from OVA-sensitized mice (CD8OVA) to sensitized recipients reduced serum IgE anti-OVA production by roughly 50%. Furthermore, studies of in vitro Ig production indicated that mononuclear cells from recipients of CD8 cells (CD8OVA > CD8PBS) produced less IgE and IgG1 antibodies, whereas in vitro IgG2a production was enhanced. The suppression of IgE production in recipients of CD8OVA T cells was associated with the failure to respond to intradermal challenge with OVA. The increase in AR found in sensitized mice was prevented after transfer of CD8OVA cells. When CD8 T cells from nonimmunized animals (CD8PBS) were used for the transfer into sensitized recipients, serum anti-OVA IgE was decreased by only 20%, whereas skin test reactivity and AR were not significantly affected. The ex vivo analysis of the pattern of cytokine-producing lymphocytes by immunofluorescence microscopy indicated that the sensitization procedure increased the fraction of IFN-gamma- and IL-4-positive cells in the spleen. Further in vitro analysis demonstrated that a high percentage of CD8 T cells were positive for IFN-gamma, whereas IL-4 was produced mainly by CD4 T cells. These data suggest that CD8 T cells may play an important role in the negative regulation of IgE production and AR and that IFN-gamma may be a relevant mediator of the functions of CD8 T cells in this model.
Animals↗
Inhibition of the development of immediate hypersensitivity by staphylococcal enterotoxin B.
We investigated the ability of staphylococcal enterotoxin B (SEB) to modify the immediate hypersensitivity response induced in BALB/c mice following sensitization to ovalbumin (OVA), a response mediated by OVA-reactive V beta 8 T cells. Mice were sensitized by skin painting with OVA every second day over a period of 2 weeks. SEB, a potent activator of V beta 8+ T cells, was administered at the same site where OVA was applied (skin of the lower abdomen) following two different protocols. In protocol (A) SEB was injected intradermally 1 day before painting with OVA and on day 7; in protocol B, SEB was injected each time OVA was applied to the skin (eight times). SEB (but not SEA) altered the development of immediate hypersensitivity to OVA, as demonstrated by the reduction in allergen-specific IgE, decreased OVA-specific immediate skin test responsiveness, and prevented the development of increased airways responsiveness after bronchial challenge with OVA. Injections of SEB did not alter the proliferative responses of local draining lymph node cells or spleen mononuclear cells to OVA, indicating that administration of SEB did not inhibit the sensitization of OVA, but shifted the immune response away from an immediate type response (IgE/IgG1) to IgG2a, IgG2b and IgG3. Although both protocols of SEB treatment did not lead to a major deletion of the V beta 8 T cell population, they did reduce the proliferative response of V beta 8+ T cells to OVA. These data indicate that the bacterial toxin SEB is capable of modifying the immediate hypersensitivity response induced by OVA by altering the functional capacity of antigen-reactive V beta 8 T cells.
Allergens↗
Suppression of cytokine-dependent human T-cell proliferation by intravenous immunoglobulin.
Human intravenous immunoglobulin (hIVIG) modifies the course of numerous immune-mediated diseases, but its specific mode of action remains unknown. In order to delineate possible immunoregulatory mechanisms, we studied the effects of hIVIG on the in vitro proliferation of human T cells. Cells from normal donors were stimulated with anti-CD3 antibody, tetanus toxoid antigen or the combination of a phorbol ester/ionomycin (P/I) and incubated with increasing concentrations of hIVIG (1 mg/ml to 10 mg/ml) for three to seven days. Addition of hIVIG inhibited anti-CD3 and tetanus but not P/I-induced proliferation in a dose-dependent manner. Addition of exogenous IL-2 to the cultures overcame the inhibitory effect of hIVIG; addition of IL-4 was ineffective. To further define the effect of hIVIG on specific cell populations, competent, purified T cells were stimulated with anti-CD3 or phorbol ester for three days in the presence of hIVIG. Addition of hIVIG blocked anti-CD3 and phorbol ester-induced stimulation of competent T cells. In cultures of competent T cells, either IL-2 or IL-4 was successful in reversing the hIVIG-induced inhibition. In these cultures, hIVIG also significantly prevented the synthesis/secretion of both IL-2 and IL-4 in PDB-stimulated competent T cells. Taken together, these data suggest that one mechanism of action of hIVIG may be through its interference with cytokine-dependent T-cell proliferation.
Cell Division↗
In vivo effects of glucocorticoids on IgE production.
Recent in vitro investigations have demonstrated that corticosteroids in combination with interleukin-4 induce the synthesis of IgE. Corticosteroids are increasingly being used to treat the inflammatory component of asthma. This has raised concern over the potential in vivo effects of corticosteroids on IgE production and the correlation of IgE-enhancing effects with clinical effects on asthma. In this study 10 patients with asthma were given a 7-day course of 20 mg of prednisone, administered orally two times a day. All of the patients had a rise in serum IgE levels after the course of prednisone (p = 0.005). Detection of specific IgE to pollen and perennial allergens demonstrated that the rise in serum IgE was polyclonal. Peripheral blood mononuclear cells from patients treated with prednisone produced increased levels of IgE in vitro when exogenous IL-4 was added to their cultures. Peripheral blood mononuclear cells obtained from patients before and after administration of prednisone revealed a significant decrease in interferon-gamma synthesis (p = 0.005), but not in interleukin-4 (p = 0.6), after the course of prednisone. These findings were paralleled by a significant decrease in the frequency of interferon-gamma (p = 0.03), but not interleukin-4 (p = 1.0) expressing cells. Despite the increase in IgE synthesis, there was a significant increase in forced expiratory volume in 1 second after the course of prednisone (p = 0.01). These data suggest that the observed rise in IgE production associated with prednisone treatment is not clinically deleterious but reflects the immunomodulatory effects of corticosteroids on T lymphocytes.
Administration, Oral↗
Development and transfer of immediate cutaneous hypersensitivity in mice exposed to aerosolized antigen.
We previously showed that BALB/c mice sensitized to ovalbumin (OVA) by brief daily inhalations of antigen over 10 consecutive days exhibit elevated antigen-specific serum IgE antibody levels and increased airways responsiveness. For the first time, we now show that animals sensitized in this fashion to either OVA or ragweed (RGW) develop immediate hypersensitivity skin test reactions when challenged 2 d after completion of the sensitization protocol. Skin testing, performed by direct assessment of wheal formation after intradermal injection of allergen, was sensitive and specific, since animals exposed to RGW by inhalation only responded to RGW, and OVA-sensitized animals responded only to OVA. Positive reactions were associated with mast cell degranulation, whereas control injections were not. Since only sensitized IgE high responder BALB/c mice but neither nonsensitized BALB/c mice nor OVA-sensitized IgE low responder SJL/J mice exhibited wheal responses, induction of OVA-specific IgE appeared to be essential for the mediation of OVA-specific immediate hypersensitivity reactions of the skin in this model. Passive cutaneous anaphylaxis (PCA) testing confirmed the presence of antigen-specific IgE in the serum. Mice that developed IgG (predominantly IgG2b) anti-OVA antibodies did not respond to OVA injection, indicating that OVA-specific IgG was not involved in this system. Further support for the role of IgE in the immediate hypersensitivity response included the wheal response to intradermal injection of anti-IgE antibody that occurred in OVA- and RGW-sensitized mice at 10-fold lower concentrations than in nonsensitized BALB/c mice and not in sensitized SJL/J mice. After transfer of mononuclear cells from peribronchial lymph nodes of OVA- or RGW-sensitized BALB/c mice, naive, syngeneic recipients developed antigen-specific IgE and specific immediate hypersensitivity responses, indicating that the local lymphoid tissue at the site of sensitization can transfer responsiveness to these allergens. These results demonstrate for the first time the ability to elicit and study IgE-mediated immediate skin hypersensitivity responses in the mouse and illustrate the association of increased antigen-specific and total serum IgE levels, airways hyperresponsiveness, and antigen-specific immediate cutaneous reactivity after sensitization to allergen via the airways.
Aerosols↗