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Modulation of Fc receptors of thymus-derived lymphocytes by antigen E in ragweed-sensitive and ragweed non-sensitive subjects.

In ragweed-sensitive and ragweed non-sensitive subjects the proportions of T lymphocytes bearing receptors for the Fc portion of IgG (T gamma) and IgM (T mu) were examined as obtained from the blood, and after treatment in vitro with ragweed antigen E or concanavalin-A. The proportion of T gamma and T mu cells, from the peripheral blood of ragweed-sensitive and ragweed non-sensitive persons, untreated in vitro, were not statistically different. However, when T cells from ragweed-sensitive subjects were exposed to ragweed antigen E, the T mu subpopulation was significantly increased (P less than 0.001) without change in the T gamma population. The reverse change occurred when cells of ragweed non-sensitive subjects were treated with antigen E; there was an increase in the T gamma subpopulation (P = 0.01) but no change in number of the T mu cells. Cells from both the sensitive and non-sensitive groups showed increase in number of T gamma and reduced numbers of T mu cells when incubated with concanavalin A. Since T gamma and T mu cells appear to have a regulatory function on B lymphocyte differentiation and antibody production, the pattern of responses of T gamma and T mu subpopulations in vitro to antigen E in ragweed-sensitive and ragweed non-sensitive subjects may reflect a difference in the cellular control of the immune response to ragweed antigen E.

Adult↗

Comparison of the in-vivo and in-vitro response to ragweed immunotherapy in children and adults with ragweed-induced rhinitis.

In order to compare results of allergen immunotherapy in paediatric and adult populations, 22 children with a history of ragweed hay fever were matched with an equal number of adults for skin sensitivity to ragweed and all were given a 1-year course of immunotherapy with a partially purified ragweed extract. Biological responses were measured by nasal challenges with ragweed before therapy was started, after 12 weekly injections and when the maintenance dose had been reached and also by methacholine bronchoprovocation tests before and after 12 months of therapy. Skin-test sensitivity to ragweed and control allergens, and ragweed-specific IgE and IgG antibody responses were measured at the same intervals as the challenges and at the end of the study. The effect of the therapy on clinical symptoms was not evaluated. Before therapy the groups of adults and children were comparable by all indices, except for TAME esterase activity in nasal washes during ragweed nasal challenge which was significantly lower in children. During treatment, mediators released during sequential nasal challenges declined to undetectable levels in most patients and changes in nasal ragweed sensitivity were comparable in both groups. Ragweed IgE increases after 12 weeks of therapy and IgG levels at maintenance therapy tended to be higher in the children, but neither difference was statistically significant. At the end of the study IgE and IgG antibody levels were comparable in both groups. Results of methacholine inhalation tests did not change significantly in either group. The decrease in skin sensitivity to ragweed was similar in both groups. We conclude that ragweed immunotherapy leads to immunological and biological consequences that are comparable in children and adults.

Adolescent↗

Combined diesel exhaust particulate and ragweed allergen challenge markedly enhances human in vivo nasal ragweed-specific IgE and skews cytokine production to a T helper cell 2-type pattern.

We have previously shown that in vivo nasal challenge with diesel exhaust particles (DEP) induces both quantitative and qualitative changes in local IgE production and stimulates generalized local cytokine production. We have now investigated the combined effects of intranasal challenge with DEP plus ragweed allergen on local humoral immune responses. We collected nasal lavages from ragweed sensitized subjects at different times after nasal challenge. As compared with challenge with ragweed alone, challenge with both DEP and ragweed induced markedly higher ragweed-specific IgE but not total IgE levels or IgE-secreting cell numbers. Total and specific IgG4 levels also were enhanced, while total IgG levels were not. Synergy was also observed between the DEP and ragweed in altering the profile of epsilon mRNAs generated by alternative splicing, mRNAs that code for different expressed IgE proteins. Intranasal challenge with ragweed alone induced inconsistent and low levels of mucosal cytokine mRNAs. In contrast, challenge with both ragweed plus DEP resulted in decreased expression for Th1-type cytokines (IFN-gamma and IL-2) but elevated expression of mRNA for other cytokines (IL-4, -5, IL-6, IL-10, IL-13). This synergy between DEP and natural allergen exposure is suggested as a key feature in increasing allergen-induced respiratory allergic disease.

Adult↗

Effect of ragweed hyperimmune human gamma globulin on in vivo and in vitro parameters of ragweed sensitivity.

The effect of ragweed hyperimmune human gamma globulin upon in vitro and in vivo parameters of ragweed sensitivity was examined. In a double-blind study, 40 ragweed sensitive patients were divided into 2 groups and received either ragweed hyperimmune human gamma globulin (treated) or normal pooled globulin (control). Parameters of ragweed sensitivity studied before and following injections of the gamma globulin included skin test and nasal provocation end point titration, specific IgE antibody as measured by the RAST, leukocyte histamine release, total serum ragweed antibody level, and total serum IgE. Changes in measured parameters varied in both groups of patients. In the "treated" patient group, 1 wk later nasal sensitivity decreased significantly, and there was a trend toward decreased histamine release from leukocytes. No discernable effect was noted upon the other parameters. Thus, with the dosage used, the parenterally administered hyperimmune gamma globulin did not influence most measurements of ragweed hypersensitivity. The concept of this therapeutic approach might warrant further investigation.

Adolescent↗

Airborne ragweed allergens: association with various particle sizes and short ragweed plant parts.

These investigations were undertaken to size airborne particles by use of a high-volume sampler and to measure the short ragweed allergen activity of airborne particles of different sizes. We found both in vitro and in vivo short ragweed allergen activity in particles of all size ranges including greater than 6, 3 to 6, 1.8 to 3, 1 to 1.8, and 0.3 to 1.0 micron in diameter. Furthermore, we investigated various parts of the short ragweed plant as possible sources of allergen. Plant parts collected before, during, and after the pollination season demonstrated significant in vitro and in vivo allergen activities. We demonstrated allergen activity in various plant parts, especially the inflorescence, as late as November 30. Appreciable ragweed allergenic activity was also associated with particles less than 1 micron in diameter. Collectively, these observations suggest persistent ragweed plant debris in different sized particles as a source of allergen in the air before and after the ragweed pollination season. This may contribute to out-of-season symptoms observed in highly ragweed-sensitive individuals.

Air Pollution↗

Leukotriene C4 release in upper respiratory mucosa during natural exposure to ragweed in ragweed-sensitive children.

With high-pressure liquid chromatography and specific radioimmunoassay, the concentration of leukotriene C4 (LTC4) was measured in nasopharyngeal secretions (NPS) of groups of children with allergic rhinitis before, during, and after the ragweed-pollen season. Increase LTC4 concentrations in NPS were noted in all the children during the pollen season; the concentration of LTC4 increased from a preseasoned mean of 1.87 +/- 0.43 ng/ml to 5.52 +/- 0.7 ng/ml at the peak of the ragweed season (p less than 0.001). The mean LTC4 concentration 2 weeks after the end of the ragweed season declined only to about 4.45 +/- 1.04 ng/ml. The seasonal variation of LTC4 concentrations and symptom scores of the children paralleled the pattern of the ragweed-pollen count. All children studied were ragweed sensitive, and six children were additionally sensitive to Alternaria (mold). The mold-sensitive children demonstrated higher concentrations of LTC4 in their NPS before and continued to have high LTC4 levels after the peak ragweed season, coinciding with peaks of mold-spore counts. Data presented in this study suggest that mast cells and other target cells in the nasal mucosa of children with allergic rhinitis produce pharmacologically active mediators, such as LTC4, during natural exposure to ragweed or Alternaria.

Adolescent↗

A double-blind, placebo-controlled trial of polymerized whole ragweed for immunotherapy of ragweed allergy.

Immunotherapy with polymerized ragweed (PRW) has been demonstrated to be safe and effective when compared with monomeric ragweed or untreated controls. To further establish the efficacy of PRW, a trial was conducted comparing PRW, placebo, and no treatment in ragweed-sensitive individuals. In a double-blind manner, 21 patients were treated before the 1981 ragweed season with 15 weekly injections of PRW totaling about 50,000 PNU and 1200 microgram antigen E, while 19 patients were treated with 15 weekly injections of a caramelized glucose and histamine placebo. An additional control group received no injections. Blood was drawn for IgE against ragweed antigen E (IgE-a-AgE) and for blocking antibody against AgE before treatment, after treatment (before season), and after season. In the untreated patients, blood was drawn before season and after season. Daily symptom score sheets were completed by patients each day of the ragweed season. Blocking antibody rose more than 40-fold with treatment (p = 0.0001) in the PRW group but was unchanged in the placebo group with treatment. IgE-a-AgE rose with PRW therapy. Clinical efficacy of PRW was again confirmed in this study. Symptom score mean in the PRW group was statistically lower than the mean in the placebo group (p = 0.022) and in the untreated group (p = 0.018). There were no systemic reactions and only minor local reactions during treatment. In summary, PRW is an improved form of immunotherapy.

Adult↗

Inhalation challenge with ragweed pollen in ragweed-sensitive asthmatics.

We reexamined the ability of inhaled ragweed pollen to induce bronchoconstriction in ragweed-sensitive asthmatic patients using a turbo-inhaler to administer pollen quantitatively. Adult subjects were selected for study on the basis of fall season asthmatic attacks, positive skin test, histamine release, RAST, and bronchial challenge responses to ragweed extract. Not one of 12 such subjects had any bronchial response to oral inhalation of whole pollen grains even when the dose was increased to 7640 pollen grains (more than the estimated maximum daily exposure in season), whereas nasal challenge by the same method produced brisk hay fever responses without bronchospasm. On the other hand, when the pollen was ground to fragments with a size range of 1 to 8 micrometers, oral inhalation produced a 35% fall in airways conductance in six of seven subjects in doses ranging from 59 to 20,000 pollen grain equivalents. Atropine pretreatment did not modify the response to pollen fragments, making an irritant response unlikely. These data, coupled with earlier observations that no more than a few pollen grains penetrate further than the larynx, raise further questions about the role of whole ragweed pollen in fall asthma in allergic patients. In addition, ragweed-allergic asthmatics appear not to have their symptoms at the time of maximum pollen load in the air. We believe that small-particle allergens other than ragweed pollen should be considered in most cases of fall seasonal asthma.

Antigens↗

In vitro release of soluble CD23 by human lymphocytes in ragweed-sensitive versus nonatopic patients following stimulation with ragweed antigen E.

BACKGROUND: Soluble CD23 is the proteolytic cleavage product of the low affinity receptor (FcERII). Functions of CD23 and its soluble products may include upregulation of IgE production and stimulation of B lymphocyte growth. METHODS: Soluble CD23 was quantitated in supernatants of lymphocytes from nine ragweed-sensitive and eight nonatopic subjects stimulated in vitro by antigen E (amb Al), crude ragweed extract, and pokeweed mitogen (PWM). RESULTS: Although PWM stimulation produced no significant difference between groups, sCD23 release was significantly elevated in the cells of nonatopic patients stimulated with antigen E and crude ragweed extract (P less than .05). CONCLUSIONS: This finding supports the concept of separate pathways of activation by antigen and mitogen for sCD23 release and suggests ragweed-sensitive and nonatopic patients have fundamental differences in the response of sCD23 release to ragweed antigen stimulation.

Adult↗

Cell-mediated immune response of ragweed-sensitive patients to ragweed antigen E. In vitro lymphocyte transformation and elaboration of lymphocyte mediators.

The in vivo and in vitro responses to ragweed antigen E were evaluated in 28 untreated atopic patients with ragweed hayfever. The methods employed included direct skin testing, measurement of total serum IgE, measurement of specific IgE anti-ragweed antibodies, leukocyte histamine release, lymphocyte transformation, and release of lymphocyte mediators (migration inhibitory factor and mitogenic factor). The patients could be divided into sensitive and insensitive groups on the basis of their in vitro reactivity to antigen E. 20 patients in the sensitive group had statistically higher levels of total serum IgE, higher levels of specific IgE anti-ragweed antibodies, and greater leukocyte sensitivity as measured by antigen-induced histamine release than did eight patients in the insensitive group. Lymphocytes from sensitive patients produced greater amounts of migration inhibitory factor and mitogenic factor when challenged by antigen E than did lymphocytes from insensitive patients. A possible role for the lymphocyte in this allergic disease is discussed. The results of this study indicate that the immune response to ragweed antigen is complex and involves components of both immediate and delayed hypersensitivity.

Adolescent↗

Quantitative inhalation bronchial challenge in ragweed hay fevery patients: a comparison with ragweed-allergic asthmatics.

Fourteen ragweed hay fever nonasthmatic patients comparably sensitive to a group of ragweed-allergic asthmatics by skin test and leukocyte histamine release were tested by quantitative inhalation bronchial challenge with ragweed extract. The provocation dose of ragweed extract producing 35% decrease in airway conductance was determined and designated PD35. PD35 values in the hay fever patients were not significantly different from PD35 values in the asthmatic group. These data suggest that carefully performed skin tests may be as diagnostically useful as bronchial challenge in routinely confirming the allergic etiology of seasonal asthma.

Airway Resistance↗

Preseasonal IgE ragweed antibody level as a predictor of response to therapy of ragweed hay fever with intranasal cromolyn sodium solution.

Intranasal administration of a 4% solution of cromolyn sodium for the treatment of ragweed hay fever was tested in an 8-week double-blind matched-pair study involving 66 patients. Patients on active drug received 5.2 mg into each nostril 6 times daily; control patients received a placebo spray. The treated group showed a significant reduction in mouth breathing (p less than 0.001), stuffy nose (p less than 0.002), runny nose (p less than 0.003), and postnasal drip (p less than 0.035). Patients receiving the active drug also reported fewer sneezing episodes (p less than 0.003) and nose blowing episodes (p less than 0.015). One patient using cromolyn solution developed nasal ulceration, tongue swelling, coughing, and wheezing. Other side effects were minimal and occurred with equal frequency in both groups. In the treated group relief of symptoms was most marked in patients with high preseasonal levels of IgE ragweed antibody. Intranasal 4% cromolyn solution appears to be an effective drug for the treatment of ragweed hay fever; measurement of the preseasonal level of IgE ragweed antibody is a useful screening test to identify patients most likely to achieve a maximal beneficial response to treatment.

Adolescent↗

The immune response of patients with ragweed hay fever treated with polymerized ragweed antigens.

This report describes the immune response of patients with ragweed hay fever treated with polymerized ragweed antigens (PRW). Their IgG antibody responses to crude ragweed extract, antigen E, antigen K, and antigen Ra3 were determined by a solid-phase radioimmunoassay. The results indicate that PRW contains an array of clinically important antigens that are available for immunologic processing and result in an immune response in patients treated with this new form of immunotherapy for ragweed hay fever.

Analysis of Variance↗

The safety and activity of polymerized ragweed: a double-blind, placebo-controlled trial in 81 patients with ragweed rhinitis.

Eighty-one patients with ragweed pollinosis were recruited for a double-blind, histamine placebo-controlled study of the safety, immunogenicity, and efficacy of 15 weekly injections of polymerized ragweed (PRW) immunotherapy totaling 1359 allergy units. Patients were paired on the basis of cutaneous end point titration to RAST standardized extracts of giant and short ragweed. One patient of each pair was randomized to receive PRW, and the other patient, a caramelized glucose histamine placebo. Symptom and medication score diaries were completed by 68 patients. All 68 patients received the full maintenance dose. No patient dropped out because of adverse reactions, and there were no systemic reactions. Except for one patient receiving placebo who developed mildly elevated liver function tests, there were no clinically significant changes in routine laboratory tests associated with injections. By Student's test on log-transformed values, blocking antibody rose significantly in the patients receiving PRW but was unchanged in those receiving placebo. By Wilcoxon paired signed-rank test, the symptom and medication scores in the patients receiving PRW were significantly lower than scores in the patients receiving placebo. This study demonstrates the safety, immunogenicity, and activity of PRW in the treatment of ragweed pollinosis.

Adult↗

Antigens of Ambrosia elatior (short ragweed) pollen. III. Crossed radioimmunoelectrophoresis of ragweed-allergic patients' sera with special attention to quantification of IgE responses.

Short ragweed allergenic extract has been studied by means of crossed radioimmunoelectrophoresis (CRIE) with the use of sera from 37 allergic patients and the relevant control sera. In this study 22 of 52 antigens, detectable in crossed immunoelectrophoresis (CIE) against polyspecific rabbit anti-ragweed IgG, were able to bind specific human IgE to their corresponding immunoprecipitates. This binding was semiquantified by comparison with the binding of a standard serum pool. Nine antigens were identified as important allergens, including the previously isolated components, AgE, AgK, and Ra6. Certain allergens (e.g., AgE, AgK, and Ag 31) bound IgE in almost all patients' sera, whereas others showed a bimodal distribution for sera of responder and nonresponder patients. The total CRIE score was found to correlate significantly both with ragweed-specific serum IgE antibody determined by RAST (rs = 0.88; p less than 0.001) and with total IgE level (rs = 0.55; p less than 0.01). Patient's CRIE scores to AgE also correlated significantly with their specific IgE antibody to AgE measured by RIA (r = 0.47; p less than 0.01) and with skin-test sensitivity to AgE (r = 0.44; p less than 0.05). It was concluded that CRIE is well suited for identification of important ragweed allergens without the previous need for laborious isolation procedures.

Adult↗

Association of class II DNA restriction fragments with responsiveness to Ambrosia artemisiifolia (short ragweed)-pollen allergen Amb a V in ragweed-allergic patients.

Human IgE and IgG antibody responsiveness to the short ragweed-pollen allergen Amb a V (formerly known as Ra5) has been found to be strongly associated with HLA-D specificities Dw2 and DR2 in ragweed-allergic white individuals. To study the molecular basis of these associations, restriction fragment length polymorphism (RFLP) mapping was performed on a group of 45 white ragweed-allergic patients with full-length HLA-DR beta, DQ beta, and DQ alpha cDNA probes. The data on 41 of these subjects were used for the purposes of statistical analysis. With the DR beta probe, we found that the presence of three polymorphic restriction fragments correlated with responsiveness to Amb a V and with the DR2 specificity, namely, a 6.5 kb Eco RI fragment, a 9.4 kb Hind III fragment, and a 2.2 kb Hind III fragment. The presence of four fragments detected with the DQ beta probe correlated with responsiveness to Amb a V and with Dw2 specificity: a 2.3 kb Eco RI fragment, a 13.0 kb Pst I fragment, a 2.9 kb Taq I fragment, and a 5.2 kb Eco RV fragment. The DR beta Eco RI 6.5 kb and the DQ beta Eco RI 2.3 kb fragments were studied in detail; the concordant presence of these fragments was even more strongly associated with responsiveness to Amb a V. Fifteen of 17 responders had both fragments, whereas only one of 24 nonresponders had both fragments (p = 5 x 10(-7). This is the first time that such an association has been found between a person's immune response to a well-defined antigen and a set of HLA class II DNA restriction fragments.

Adult↗

Regulation of the human immune response to ragweed pollen by immunotherapy. A controlled trial comparing the effect of immunosuppressive peptic fragments of short ragweed with standard treatment.

A new allergenic preparation consisting of peptic fragments of short ragweed has been tested for its clinical effectiveness. Such enzymatically derived fragments have been shown in prior murine studies to retain the T epitopes of the original allergen but to have a severe reduction in the number of B epitopes. Three groups of ragweed hayfever patients were placed on pre-seasonal immunotherapy. One group received a conventional ragweed preparation that had been enriched for antigen E (Amb a I), designated as Pool 2. The second group was given fragments of Pool 2 (fSRW) prepared by peptic digestion and the third group was injected with histamine as a placebo. Groups treated with the fSRW and Pool 2 had significantly reduced symptom-medication scores compared with the placebo-treatment group. However, fSRW-treated patients fared significantly better than Pool 2 patients (P less than 0.02). fSRW injections caused a significant rise in preseasonal specific IgG, antibodies as well as suppression of the seasonal anamnestic specific IgE increase. Similar, but not quite as marked changes occurred with Pool 2 treatment. fSRW was well tolerated and non-toxic. Thus, allergen modification by enzymatic degradation, as demonstrated here, appears to be a promising new approach for allergen immunotherapy.

Adult↗