Randomized double-blind, placebo-controlled trial of sublingual immunotherapy with a Pru p 3 quantified peach extract

Background:  Peach allergy is highly prevalent in the Mediterranean area; it is persistent and potentially severe, and therefore a prime target for immunotherapy. We aimed to study the efficacy and safety of sublingual immunotherapy (SLIT) with a peach extract quantified in mass units for Pru p 3, the peach lipid transfer protein.
Methods:  Randomized, double-blind, placebo-controlled (DBPC) clinical trial. The main efficacy outcome was the change in the response to a DBPC food challenge (DBPCFC) with peach. Secondary efficacy outcomes were the changes in skin prick test (SPT), and in specific immunoglobulin E (IgE) and IgG₄ to Pru p 3. Tolerance was assessed with a careful recording of adverse events.
Results:  After 6 months of SLIT, the active group tolerated a significantly higher amount of peach (three- to ninefold), presented a significant decrease (5.3 times) in SPT, and a significant increase in IgE and IgG₄ to Pru p 3. No significant changes were observed within the placebo group. Statistically significant inter-group differences were only observed in the SPT and IgG₄ responses. No serious adverse events were reported. Systemic reactions were mild, and observed with a similar frequency in both groups. Local reactions were significantly more frequent in the active group (three times) and 95% of them restricted to the oral cavity.
Conclusion:  In this first exploratory clinical trial, SLIT for peach allergy seems to be a promising therapeutic option that could modify the clinical reactivity of the patients to peach intake and the underlying immunological response with a good tolerance.     

Secondary IgE Responses In Vivo are Predominantly Generated Via γ1ɛ-Double Positive B Cells

We have recently developed a model in which mice were treated with 1L-4 after primary immunization, resulting in elevated total serum IgG₁ and IgE levels, but decreased antigen-specific levels and memory formation for these isotypes. In this report, we describe that these effects of IL-4 are mediated at the B cell and not the T-cell level. Major changes occurred in the γ1ɛ-double positive B-cell population which is increased as a result of IL-4 treatment. Moreover, it is shown that γ1ɛ-double positive B cells can develop in vitro out of γ1-positive primed B cells and that these double positive cells can differentiate into IgG₁- and IgE-secreting cells. The existence of γ1ɛ-double positive memory B cells can explain the differences in cytokine dependence of TNP-specific memory IgG₁ and IgE responses found after adoptively transferring primed spleen cells into irradiated naive recipients. Whereas the IL-4 independent TNP-specific memory IgG₁ responses could be blocked efficiently by neutralizing IL-5 and IL-6, TNP-specific memory IgE responses were virtually not susceptible to such treatment. These IgE responses were also not susceptible to IFN-γ, used in doses that could inhibit the primary IgE response. Inhibition of the TNP-specific memory IgG₁ response by neutralizing IL-5 and IL-6 is accompanied by a 10-fold increase of the IL-4 independent TNP-specific IgE memory response. These data indicate that secondary IgE responses primarily result from B cells that are either switched to IgG₁, or are double positive for IgG₁ and IgE, thereby suggesting a minor role for ɛ-single positive B cells in secondary IgE responses.     

Clinical and immunological effects of immunotherapy with alum-absorbed grass allergoid in grass-pollen-induced hay fever

A double-blind, placebo-controlled study of immunotherapy was conducted in 19 patients with grass-pollen hay fever to evaluate the efficacy and safety of a formalinized depot grass allergoid. The patients were assessed before and during IT by clinical (symptom-medication scores during the grass- pollen season, specific nasal and skin reactivity) and immunological (specific IgE, IgG, IgG₁ and IgG₄ antibodies) parameters. High doses of grass allergoid, corresponding to a cumulative pre-seasonal dosage of 46050 PNU, were administered, with only one systemic reaction. The actively treated patients had significantly lower symptom-medication scores than placebo ( p < 0.01) during the month of May and showed a significant decrease in specific skin ( p < 0.01) and nasal ( p < 0.05) reactivity, and a significant early increase in specific IgE ( p < 0.01), IgG ( p < 0.0005), IgG₁ ( p < 0.001) and IgG₄ ( p < 0.05), with a subsequent decrease of IgE and IgG₁. No differences were detected in any of these parameters in the placebo group. A correlation was found between high IgG₄/IgG₁ ratio and the specific skin reactivity decrease (r = 0.691, p < 0.05), whereas a high IgG₄/IgG₁, ratio was associated with higher symptom-medication scores (r = 0.654, p < 0.05). Possible explanations of these apparent discrepancies are proposed.     

Prolonged In Vivo IL-4 Treatment Inhibits Antigen-Specific IgG1 and IgE Formation

IL-4 is obligatory for primary IgE responses, whereas primary IgG, and secondary IgE responses are partially IL-4 independent. To investigate the effect of IL-4 on the antigen-specific memory formation for these isotypes, BALB/c mice were treated after primary TNP-KLH immunization with recombinant IL-4 for a period of 4 months. This prolonged presence of a high IL-4 level resulted in increased serum levels of total IgG₁ and IgE, whereas total IgG_2a did not change. The expression of CD23, but not J-A^d, increased on the splenic B cells. IL-4 treatment did not affect the IL-4 production by Con A stimulated spleen cells, whereas it did decrease the IFN-γ production. In the same mice the TNP-specific IgG₁ and IgE serum levels, however, were decreased. Similar results were found when the antigen was continuously present during the IL-4 treatment. Furthermore, it was shown that IL-4 decreased the formation of IgG₁, and IgE memory cells. These results point to different effects of IL-4 in regulating antigen-specific and bystander responses.     

Enzyme-linked immunosorbent assay for detection of antibodies to the unmodified beta-lactam ring

Dose- and pH- dependent carbodiimide-mediated coupling of Penicillin-G to polystyrene microtiter-plates that leaves the beta-lactam ring unchanged is described. A new ELISA method was developed using Penicillin-G coated plates. The binding of 3 different monoclonal antibodies as well as human IgG antibodies of the IgG₁ and IgG₃ subclasses is demonstrated, whereas IgG₂, IgG₄ and IgE antibodies did not bind. Thus, covalently coupled Penicillin-G can be used to study the immune-response to the unchanged β-lactam ring in patients receiving penicillin therapy. The new method is complementary to hitherto described techniques, which generally only allow detection of antibodies binding to penicilloyl-groups.     

Allotype-Associated Differences in Concentrations of Human IgA2

Concentrations of immunoglobulin (Ig)A₂ were determined in 176 Finnish blood donor sera. Their IgA, IgM, IgE, IgG₁, IgG₂, IgG₃ and IgG₄ concentrations and Gm allotypes had been determined earlier. The mean concentration of IgA₂ was higher in individuals carrying the Gm(ax) allele (0.15 g/l) than in those negative for Gm(x) (0.103 g/l). The difference was statistically significant ( P  = 0.006). As ≥ 70% of IgA was usually IgA₁, its concentration could be calculated fairly reliably by subtracting the IgA₂ value from the IgA value. The mean IgA₁ concentration (2.03 g/l) seemed to be independent of the Gm allotypes.     

Early-life co-administration of cockroach allergen and endotoxin augments pulmonary and systemic responses

Background Environmental exposures to cockroach allergen and endotoxin are recognized epidemiological risk factors for the early development of allergies and asthma in children. Because of this, it is important to examine the role of early-life concurrent inhalation exposures to cockroach allergen and endotoxin in the pathogenesis of allergic airways disease.
Objective We examined the effects of repeated concomitant endotoxin and cockroach allergen inhalation on the pulmonary and systemic immune responses of newborn and juvenile mice.
Methods C3H/HeBFeJ mice were exposed to inhaled endotoxin and cockroach allergen via intranasal instillation from day 2 to 21 after birth, and systemic and pulmonary responses were examined in serum, bronchoalveolar lavage fluid, and lung tissue.
Results Cockroach allergen exposures induced pulmonary eosinophilic inflammation, total and allergen-specific IgE, IgG₁, and IgG_2a production, and alveolar remodelling. Co-exposures with endotoxin and cockroach allergen significantly increased serum IgE and IgG₁, lung inflammation, and alveolar wall thickness, and decreased airspace volume density. Importantly, compared with exposures with individual substances, the responses to co-exposures were more than additive.
Conclusions Repeated inhalation exposures of neonatal and juvenile mice to endotoxin and cockroach allergen increased the pulmonary inflammatory and systemic immune responses in a synergistic manner and enhanced alveolar remodelling in the developing lung. These data underscore the importance of evaluating the effect of multiple, concurrent environmental exposures, and of using an experimental model that incorporates clinically relevant timing and route of exposures.     

Carbohydrate-based particles reduce allergic inflammation in a mouse model for cat allergy

Background:  Allergen-specific immunotherapy (ASIT) is the only treatment of allergic disease that gives long-lasting relief of symptoms. However, concerns for safety and efficiency have highlighted the need for improvement of the therapy. We have previously suggested carbohydrate-based particles (CBPs) as a novel adjuvant and allergen carrier for ASIT. Our aim of this study was to evaluate the therapeutic potential of CBPs in ASIT, employing a mouse model for cat allergy.
Methods:  BALB/c mice were subcutaneously immunized with the recombinant (r) cat allergen Fel d 1 followed by intranasal challenge with cat dander extract (CDE). The sensitized mice were therapeutically treated with rFel d 1 covalently coupled to CBPs (CBP-rFel d 1). Airway hyper-reactivity (AHR), infiltration of leucocytes in bronchoalveolar lavage (BAL) fluid, allergen-specific serum immunoglobulin levels and in vitro splenocyte responses were evaluated.
Results:  Mice treated with CBP-rFel d 1 showed reduced features of allergic inflammation. They responded with (i) significantly decreased AHR and infiltration of eosinophils in BAL fluid after CDE challenge, (ii) the serum level of rFel d 1-specific IgE was reduced and the level of IgG₂a was more pronounced after CBP-rFel d 1 treatment, and (iii) there was also a tendency of decreased allergen-specific cellular response.
Conclusions:  Carbohydrate-based particles are effective tools as adjuvant and allergen carriers for use in ASIT and constitutes a promising strategy to improve allergy treatment.     

Higher immunoglobulin E antibody levels to recombinant Fel d 1 in cat-allergic children with asthma compared with rhinoconjunctivitis

Background Current diagnosis of allergy and asthma to cat is confirmed using cat dander extract (CDE). We have previously engineered a recombinant major cat allergen, rFel d 1, with properties identical to the natural molecule.
Objective The aim of the study was to evaluate IgE and IgG4 antibodies to rFel d 1 among sera from cat-allergic children and adults suffering from asthma and/or rhinoconjunctivitis (RC) in populations from Sweden and Austria.
Methods Cat-allergic children and adults from Sweden ( n =27 and 31, respectively) and Austria ( n =41 and 41) with RC and/or asthma were selected. Sera were tested for IgE and IgG4 antibodies to CDE and rFel d 1 by CAP, and IgE to rFel d 1 by ELISA. Healthy subjects and non-cat-allergic patients ( n =75) were included as controls.
Results There was a high correlation between IgE responses to rFel d 1 and CDE among the 140 patients ( r _s=0.85, P <0.001); however, measured levels to rFel d 1 were on average 30% higher ( P <0.0001). Ninety-eight percent of patients and none of the controls showed IgE to rFel d 1 and there was a threefold increased risk of asthma for half of the children with the highest IgE levels [odds ratio 3.23; 95% confidence interval (CI), 1.19–8.79] by ELISA. IgE responses to rFel d 1 among children with asthma were higher (median 19.4 kU/L) compared with children with RC (median 6.6 kU/L, P <0.05) and adults with asthma (median 3.0 kU/L, P <0.01). Furthermore, children with asthma displayed higher IgG4 levels than the asthmatic adults.
Conclusion A single recombinant molecule, rFel d 1, is at least as sensitive for in vitro diagnostics of cat allergy as the current extract-based test. Elevated IgE antibody levels to Fel d 1 are suggested to be a risk factor for asthma in cat-allergic children.     

Longitudinal study on the relationship between cat allergen and endotoxin exposure, sensitization, cat-specific IgG and development of asthma in childhood--report of the German Multicentre Allergy Study (MAS 90)

BACKGROUND: Controversial data have emerged regarding the question whether cat exposure in childhood favours or decreases the risk of sensitization and allergic airway disease. In a prospective birth-cohort study, we assessed the association between longitudinal cat allergen exposure, sensitization (immunoglobulin E, IgE), IgG antibody (ab) levels to cat and the development of asthma in children up to the age of 10 years. METHODS: Of 1314 newborn infants enrolled in five German cities in 1990, follow-up data at age 10 years were available for 750 children. Assessments included yearly measurements of specific serum IgE to cat and at age 6 and 18 months, 3, 4 and 10 years measurement of cat allergen Fel d 1 in house dust samples. Additionally, Fel d 1-specific IgG ab were determined in 378 serum samples of 207 children. Endotoxin exposure in mattress dust was measured in a subgroup of 153 children at age 10 years. From age 4 years on, International Study of Asthma and Allergy in Childhood (ISAAC) questionnaires were completed yearly in order to assess the prevalence of wheeze and asthma. RESULTS: Serum IgG-levels to cat showed a large variation, however, intraindividually values showed rather constant concentration over a longer time period. The IgG levels at school-age correlated with cat allergen exposure during the first 2 years of life. Specific IgE to cat was clearly associated with wheeze ever, current wheeze and bronchial hyperresponsiveness (BHR), this was also observed for children with specific IgE ab to cat (>0.35 kU/l) plus IgG levels above 125 U/ml. A large percentage of very highly exposed children showed high IgG but no IgE responses to cat, however, not all highly exposed children were found to be protected from sensitization. Children with IgG but without IgE ab to cat showed the lowest prevalence of wheeze ever and current wheeze despite high cat allergen exposure, however, this trend did not achieve significance. While homes of cat owners showed higher Fel d 1 concentrations than homes without cats, homes of cat owners were not found to have higher endotoxin levels in carpet dust samples than homes without cats. CONCLUSIONS: We could confirm that high cat allergen exposure in a cohort with lower community prevalence of cats is associated with higher serum IgG and IgE levels to cat in schoolchildren. Sensitization to cat allergen (IgE) is a risk factor for childhood asthma. While exposure to cat allergen during infancy is associated with sensitization (IgE), only in the very highly exposed children the likelihood of sensitization (IgE) is decreased and high IgG levels to cat without IgE were associated with low risk of wheeze. However, cat-specific IgG ab levels did not protect children with IgE-mediated sensitization from wheeze.     

Effect of environmental allergen sensitization on asthma morbidity in inner-city asthmatic children

Background Asthma causes significant morbidity in children, and studies have demonstrated that environmental allergies contribute to increased asthma morbidity.
Objective We investigated the differences between allergen skin tests and specific IgE (SIgE) and the role of IgG in regards to allergen exposure levels, and asthma morbidity in inner-city children.
Methods Five hundred and six serum samples from the National Cooperative Inner City Asthma Study (NCICAS) were evaluated for SIgE to cockroach ( Blattella germanica ), dust mite ( Dermatophagoides farinae ), and Alternaria as well as specific IgG (SIgG) and IgG₄ to cockroach ( B. germanica) and total IgE levels. Associations between sensitization to these allergens, exposures, and asthma morbidity were determined.
Results Sensitization to environmental allergens and total IgE correlated with increased health care and medication use, but not with symptoms of wheeze. Sensitization with exposure to cockroach was associated with increased asthma morbidity, whereas dust mite sensitization was correlated with asthma morbidity independent of exposure. There was also a strong correlation between SIgE levels and skin test results, but the tests did not always agree. The relationship between SIgE and asthma morbidity is linear with no obvious cutoff value. Increased Bla g 1 in the home was a good predictor for sensitization; however, this relationship was not demonstrated for Der f 1. Cockroach SIgG correlated with increased health care use, however, there was no modifying effect of SIgG or SIgG₄ on the association between cockroach SIgE and asthma morbidity.
Conclusions SIgE levels and skin prick test results to environmental allergens can serve as markers of severe asthma for inner-city children. Asthma morbidity increased in a linear manner with SIgE levels. IgG was not an important predictor or modifier of asthma morbidity.     

Efficacy of grass pollen sublingual immunotherapy for three consecutive seasons and after cessation of treatment: the ECRIT study

Background:  Data supporting a carry-over effect with sublingual immunotherapy (SLIT) are scarce. This randomized, double-blind, placebo-controlled study evaluated the efficacy, carry-over effect and safety of grass pollen SLIT using co-seasonal treatment.
Methods:  Patients (7.9–64.7 years) with grass pollen allergy received ultra-rush titration with increasing doses (30, 90, 150 and 300 IR) of a 5-grass pollen mixture every 20 min at the start of the pollen seasons, followed by 300 IR daily until the end of the pollen seasons. A baseline season (no SLIT) was followed by three consecutive treatment seasons and one follow-up season. Symptoms, medication and adverse events were documented and specific immunoglobulin (Ig)E and IgG₄ measured.
Results:  Data were analysed for 183 of the 213 randomized patients. Mean treatment duration varied between seasons (81.8−92.7 days). Combined scores (symptoms and medication) improved progressively across treatment seasons (up to 44.7% improvement for SLIT compared with baseline) and fluctuated between −11.3% and −14.8% for placebo ( P  < 0.05). Similar changes were observed for symptom scores, with a successive decrease of 39.7% (SLIT) and fluctuations between +13.6% and −1.51% for placebo ( P  < 0.05). Combined score ( P  = 0.0508) and symptom score improvements ( P  = 0.0144) with SLIT continued during follow up. Increases in specific IgG₄ observed in the first season were sustained for SLIT vs placebo throughout treatment ( P  = 0.0001). Titration and daily SLIT were well tolerated. No serious systemic or anaphylactic reactions were reported.
Conclusions:  Seasonal SLIT with ultra-rush titration is well tolerated and effective from the first treatment season onwards. These data indicate a carry-over effect of seasonal SLIT.     

Efficacy of grass pollen sublingual immunotherapy for three consecutive seasons and after cessation of treatment: the ECRIT study

Background:  Data supporting a carry-over effect with sublingual immunotherapy (SLIT) are scarce. This randomized, double-blind, placebo-controlled study evaluated the efficacy, carry-over effect and safety of grass pollen SLIT using co-seasonal treatment.
Methods:  Patients (7.9–64.7 years) with grass pollen allergy received ultra-rush titration with increasing doses (30, 90, 150 and 300 IR) of a 5-grass pollen mixture every 20 min at the start of the pollen seasons, followed by 300 IR daily until the end of the pollen seasons. A baseline season (no SLIT) was followed by three consecutive treatment seasons and one follow-up season. Symptoms, medication and adverse events were documented and specific immunoglobulin (Ig)E and IgG₄ measured.
Results:  Data were analysed for 183 of the 213 randomized patients. Mean treatment duration varied between seasons (81.8−92.7 days). Combined scores (symptoms and medication) improved progressively across treatment seasons (up to 44.7% improvement for SLIT compared with baseline) and fluctuated between −11.3% and −14.8% for placebo ( P  < 0.05). Similar changes were observed for symptom scores, with a successive decrease of 39.7% (SLIT) and fluctuations between +13.6% and −1.51% for placebo ( P  < 0.05). Combined score ( P  = 0.0508) and symptom score improvements ( P  = 0.0144) with SLIT continued during follow up. Increases in specific IgG₄ observed in the first season were sustained for SLIT vs placebo throughout treatment ( P  = 0.0001). Titration and daily SLIT were well tolerated. No serious systemic or anaphylactic reactions were reported.
Conclusions:  Seasonal SLIT with ultra-rush titration is well tolerated and effective from the first treatment season onwards. These data indicate a carry-over effect of seasonal SLIT.     

High prevalence of sensitization to cat allergen among Japanese children with asthma, living without cats

BACKGROUND: Cat allergy is common among children with asthma. Many cat-allergic patients in Japan and elsewhere do not keep cats, but nonetheless become sensitized through environmental exposure to cat allergen. OBJECTIVE: To assess the frequency of cat allergy and cat-specific immunoglobulin E (IgE) and immunoglobulin G (IgG) antibody responses in young Japanese patients with asthma in relation to self-reported cat exposure and Fel d 1 levels in dust samples. METHODS: Cat dander-specific IgE antibody was measured in sera from asthma patients using the CAP system. IgE and IgG antibody to Fel d 1 was measured by antigen binding radioimmunoassay and by chimeric enzyme immunoassay. Fel d 1 levels in dust samples from a subset of patients' homes were measured by monoclonal antibody-based enzyme immunoassay. RESULTS: Cat-specific IgE (CAP class>/=2) was found in sera from 70% of 44 patients who kept cats and 34% of 394 patients who had never kept cats. The prevalence of sensitization increased progressively to age 6 years (40%: positive), and then increased gradually to age 16 years (approximately 60%: positive) in patients who had never kept cats. There was an excellent correlation between cat CAP values and IgE levels to Fel d 1. The absolute amount of IgE antibody to Fel d 1 ranged from 0.01 to 15.6% of total IgE. Most patients who did not keep cats were exposed to Fel d 1 levels ranging from 0.07-8 microg/g dust. CONCLUSIONS: Sensitization to cat allergen is common among young asthmatic patients in Japan, even among patients who do not keep cats. Use of CAP and the chimeric enzyme-linked immunosorbent assay allows accurate diagnosis of cat allergy and quantification of specific IgE antibody levels.     

Antigen-Induced Bronchial Anaphylaxis in Actively Sensitized Guinea-Pigs Pattern of Response in Relation to Immunization Regimen

This work studies the temporal development of the acute anaphylactic bronchoconstriction in guinea-pigs sensitized to ovalbtiin by different regimens, including IgE-antibody promoting ones. The results show that guinea-pigs sensitized with low amounts (1-10μg) of ovalbumin together with alum produce the most pronounced bronchospasm when challenged with an intravenous injection of a low dose of antigen. Examination of the antibody classes by PCA technique shows that guinea-pigs sensitized with small amounts of antigen together with alum produce IgE and IgG₁ antibodies. However, in sera from animals immunized with large amounts of antigen, only IgG₁ antibodies could be detected.     

Isolation of a Fragment, Fh, Corresponding to the Hinge Region of Human IgG3

An Fh fragment corresponding to the hinge region of IgG₃ has been isolated by J single α-chymotrypsin treatment of whole IgG₃ Various combinations of two enzymes have also been used, but with somewhat lower yield and less purity The isolated Fh fragment has features similar to those of the bound hinge region in the intact IgG₃ and its F(ab ' )₂ and Fch fragments. The Fh fragment has a char acteristically high content of cystine and proline and seems to lack aromatic amino acids     

Inhibition of Antibody-Dependent Human Lymphocyte-Mediated Cytotoxicity by Immunoglobulin Classes, IgG Subclasses, and IgG Fragments

The cytotoxicity of human peripheral blood lymphocytes against chicken erythrocytes sensitized by rabbit antibodies was inhibited by human immunoglobulin and immunoglobulin fragments. Myeloma proteins isolated in dimeric state or aggregated by heat treatment inhibited better than the corresponding monomeric proteins. Strong inhibition was observed with IgG1 and IgG3, and with IgG₂ after aggregation, while IgG₄ inhibited very little. No inhibition was found with IgM, IgA. IgD and IgE. The F(ab')₂. and Fab fragments of IgG inhibited poorly or not at all. While- considerable inhibition was observed with the Fc fragment, the pFc' fragment, which roughly corresponds to the C-terminal half of the Fc portion, showed little inhibitory capacity. A fragment isolated from IgG3, containing an extension of the N-terminal part of Fc (the Fch fragment), was an even better inhibitor than tin Fc fragment. The inhibitory capacity of the Fch and Fc fragments was greatly diminished following partial reduction and alkylation On the basis of the inhibitory pattern of IgG fragments, it is suggested that the region on the immunoglobulin molecule involved in binding to the Fc receptor of the effector lymphocytic cell may be located within the CH2 domain.     

The size of the disease relevant IgE antibody fraction in relation to 'total-IgE' predicts the efficacy of anti-IgE (Xolair®) treatment

Background:  Some patients with allergic asthma treated with anti-IgE (Xolair^®) do not become symptom free. Better criteria for response assessment than allergy skin tests or IgE determination are needed. The impact of the size of the disease relevant allergen-specific IgE antibody fraction, i.e. the percentage of IgE antibody of total IgE, was evaluated in cat allergic patients treated with the recommended doses of Xolair^®. Results were measured as changes in basophil allergen threshold sensitivity (CD-sens).
Methods:  In a double-blind placebo controlled trial 20 patients with a high (>3.8%) and 18 with a low (<1%) percentage of IgE antibodies to cat were given Xolair^® for 16 weeks and the change in CD-sens was compared to 11 and 10 patients, respectively, in each group receiving placebo.
Results:  The CD-sens dropped significantly in both the high ( P  < 0.001) and low ( P  < 0.001) group on Xolair^® but did not change significantly after placebo. For Xolair^®-treated patients, at the end of the trial there was a highly significant ( P  < 0.001) difference in CD-sens between the high group, where no patients, and the low group, where 13/18 patients, had become negative.
Conclusions:  The currently recommended doses of Xolair^® very efficiently eliminate IgE antibodies if the IgE antibody fraction is <1% of total IgE but has not enough effect on allergen sensitivity if the fraction is >3–4%. Further studies will show if increased doses of Xolair^® would help also these patients, who seem to represent about 1/3 of the patient population.     

Evidence for a Fel d I-like molecule in the "big cats" (Felidae species).

In this study, we investigated the cross-reactivity pattern of IgE and IgG4 antibodies to the major feline allergen, Fel d I. We studied the IgE and IgG4 response of 11 cat-allergic patients against Fel d I-like structures in eight members of the Felidae family: ocelot, puma, serval, siberian tiger, lion, jaguar, snow leopard, and caracal. Hair from these "big cats" was collected, extracted, and used in a RAST system and histamine-release test. By means of a RAST-inhibition assay with affinity-purified Fel d I from cat dander, it was established that, in the Felidae species, a Fel d I equivalent is present that reacts with IgE and IgG4 antibodies. We found that all patients had cross-reacting IgE antibodies to seven of the Felidae tested; no IgE antibodies reactive with the caracal were found. Eight of 10 patients with IgG4 antibodies directed to cat dander also had IgG4 antibodies directed to several Felidae species, including the caracal. However, the correlation between the IgE and the IgG4 antibody specificity was low, indicating that, in the case of Fel d I IgE and IgG4, antibodies do not necessarily have the same specificity.     

High-dose allergen exposure leads to tolerance

Reports of decreased sensitization to cat allergen (Fel d 1) among individuals living with a cat or subjects exposed to high-dose cat allergen may be explained by the development of a form of high-dose tolerance resulting from natural exposure to an inhalant allergen. Although the epidemiological data regarding the relationship between exposure and sensitization to Fel d 1 are conflicting, the ability for high-dose Fel d 1 to induce a characteristic nonallergic immune response with a distinctive serum antibody profile has been established. Definition of this modified T-helper (Th)2 response to cat allergen, coupled with the renewed interest in regulatory T cells within the immunology field, has provided an avenue for exploring the mechanism by which IgE antibody-mediated responses are controlled. There is mounting evidence to suggest that the modified Th2 response is a variation of the allergic response and that the modified Th2-allergic axis is influenced by allergen dose and genetics. This article discusses putative immune mechanisms of tolerance within the context of an allergen-specific system. The relevance of high-dose allergen exposure and alternate factors such as endotoxin to the development of tolerance is considered. Fel d 1 exhibits unique molecular and immunological characteristics that may contribute to its tolerogenic properties. Major T-cell epitopes of Fel d 1 that preferentially induce regulatory factors have been defined. Furthermore, hightiter IgE antibody responses associated with atopic dermatitis are characterized by a defect in the T-cell repertoire that is specific to these epitopes. Identification of Fel d 1 epitopes that induce interleukin-10 may provide new targets for treatment.