Efficacy Of Specific Immunotherapy Research Articles

Genetically modified allergens.

For more than 90 years, allergen-specific immunotherapy, the only causative allergy treatment, has remained basically unchanged. The development of molecular biology techniques has led to the preparation of individual recombinant allergens from the most important allergen sources. Recombinant allergens can be used to determine the individual sensitization profile of allergic patients and have allowed the development of novel therapeutic tools. This article summarizes data on genetically modified recombinant allergen derivatives with reduced allergenic activity, which may be used to improve the safety and efficacy of specific immunotherapy.

Effect of tree pollen specific, subcutaneous immunotherapy on the oral allergy syndrome to apple and hazelnut

The efficacy of specific immunotherapy (SIT) in pollen allergy is well established. However, its effect on pollen associated food allergy particularly the oral allergy syndrome (OAS) is not definitely ascertained. The purpose of this controlled prospective study was to investigate whether SIT with tree pollen, mainly birch, has an effect on OAS induced by apple or hazelnut in birch pollen-allergic individuals. Twenty-seven birch pollen-allergic subjects with OAS induced by apple or hazelnut underwent open oral provocation tests (OPT) with increasing doses (1 to 128 g) of fresh apple or ground hazelnut 1 year apart. Fifteen of 27 subjects were treated with SIT and 12 were not. Skin-prick test with birch pollen, apple and hazelnut, and specific serum IgE, IgG and IgG4 to rBet v 1, apple and hazelnut were determined. Thirteen of 15 (87%) SIT-treated subjects could eat significantly (P <0.001) more of apple or hazelnut without any symptoms/signs. The average tolerated quantity increased from 12.6 to 32.6 g apple after 1 year in this group. In contrast, only one of 12 (8%) individuals without SIT was able to consume a higher amount without symptoms. On evaluating laboratory parameters, only IgG4 antibodies to rBet v 1 were found to be significantly (P <0.01) increased in the SIT-treated group after 1 year. The study shows that SIT with extracts containing birch pollen has a positive impact on OAS to apple or hazelnut in birch pollen-allergic individuals. In spite of this outcome, the amount of apple/hazelnut tolerated is still small. Thus, the effect of SIT on the patients' management of OAS remains limited.

The blocking activity of birch pollen-specific immunotherapy-induced IgG4 is not qualitatively superior to that of other IgG subclasses

Allergen-specific IgG antibodies induced by specific immunotherapy (SIT) interfere with the allergen–IgE interaction, and act as blocking antibodies in vitro. It has been hypothesised that IgG4, as opposed to other IgG subclasses, is particularly important in this function, which may play a role for the clinical efficacy of SIT. In this study, fractionated serum samples from 14 SIT-treated birch pollen allergic individuals enabled determination of the inhibitory capacity of IgG4 alone versus non-IgG4 IgG. Allergen-binding activities of IgG and the IgG-mediated inhibition of allergen binding to autologous IgE were detected using 125I-labelled rBet v 1.2801, a recombinant variant of the major allergen of Betula verrucosa pollen. Results show that IgG4-depletion resulted in equivalent reductions in binding and blocking activities. In contrast, a significant but less than two-fold higher relative blocking activity was found in the purified IgG4 fraction. There was no significant difference in the binding avidities (1/ K d) measured in the two IgG fractions. Thus, it appears that SIT-induced specific IgG4 contributes to the IgG blocking of allergen binding to IgE in a simple quantitative manner and not by a particular intrinsic blocking activity.

Adhesion molecules and efficacy of specific immunotherapy

Rationale Adhesion molecules evaluation may be used as an inflammation marker in allergy and to evaluate specific immunotherapy (SIT) efficacy. We evaluated the evolution of ICAM-1 and VCAM-1 in their soluble and cellular forms during SIT in patients allergic to house dust mite ( Dermatophagoides pteronyssinus-D.pter.). Methods 3 groups of patients with allergic rhinitis confirmed by clinically history, skin tests and specific IgE (sIgE). Group I: 20 patients (15-55 years old), 8 females, 12 males with SIT, performed with a modified extract of D.pter, Depigoid®. Group II: 20 patients (15-55 years old) 8 females, 12 males, with SIT modified to 1/10 of the concentration. Control group: 15 patients (15-55 years old), 7 females, 8 males, with respiratory allergy without SIT. Serum levels of ICAM-1 and VCAM-1: ELISA R&D. Cellular adhesion molecules: flow cytometry (FACSCalibur) CD54, CD106. Blood collected in all patients before SIT (T0), after 6 months (T1), after 1 year (T2). Results Group I: mean serum level of ICAM-1: T0-372,6ng/ml; T1-324,3ng/ml; T2-265,31ng/ml (p<0.001); VCAM-1: T0-677,36ng/ml; T1-605.09ng/ml; T2-523,76ng/ml (p=0.001). Mean of % for CD54: T0-20,84; T1-23,72; T2-27,48 (p=0.04). Group II: ICAM-1: T0- 370.5ng/ml; T1-308,4ng/ml; T2-209,5ng/ml (p<0.001). VCAM-1: T0-672,4ng/ml; T1-602.9ng/ml; T2-503,56ng/ml (p=0.002). CD54: T0-23,96; T1-27,76, T2-27,52 (p=0.102). Control group: ICAM-1: T0-363,16ng/ml; T1-350,41ng/ml; T2-376,5ng/ml (p=0.303), VCAM-1: T0-671,58ng/ml; T1-640.43ng/ml; T2-678,5ng/ml (p=0.412); CD54: T0-16,12; T1-21,04; T2-22,40 (p=0.06). CD106 negative in all groups. Conclusions After 1 year of SIT, there is a significant decrease of the serum levels of ICAM-1 and VCAM-1, supporting SIT efficacy. Mean values of CD54 in the 3 groups showed a slight increase especially in group 1. sICAM-1 and sVCAM-1 seems to be useful markers of inflammation during SIT.

The blocking activity of birch pollen specific immunotherapy induced IgG4 is not qualitatively superior to that of other IgG subclasses

Rationale Allergen specific IgG antibodies induced by specific immunotherapy (SIT) interfere with the allergen-IgE interaction, and act as blocking antibodies in vitro. It has been hypothesized that IgG4, as opposed to other IgG subclasses, is particularly important in this function, which may play a role for the clinical efficacy of SIT. In this study we compared the inhibitory capacity of IgG4 alone versus non-IgG4 IgG from SIT treated birch pollen allergic patients. Methods IgE depleted serum samples from 14 SIT-treated birch pollen allergic patients were separated into purified IgG4 and IgG4-depleted IgG. The allergen binding activities of IgG and the IgG mediated inhibition of allergen binding to autologous IgE were detected using 125I labeled rBet v 1.2801, a recombinant variant of the major allergen of Betula verrucosa pollen. Binding avidities were determined by saturation binding analysis. Results When the sera were depleted of IgG4, the ratio between inhibition and binding activities was found to be the same as in unseparated serum, indicating a simple relationship between inhibition and binding activities. In contrast, a significant, but less than two fold higher relative blocking activity was found in the purified IgG4 fraction. There was no significant difference between the binding avidities (1/K d) measured in IgG4-depleted IgG and purified IgG4. Conclusions These results suggest that SIT induced specific IgG4 contributes to the IgG mediated blocking of allergen binding to IgE in a simple quantitative manner and not by a particular intrinsic blocking activity.

Allergen immunotherapy in ENT: historical perspective

The origins of immunology and allergy are founded upon the early 19th century microbiological studies of Jenner and Pasteur. It was discovered that the immune system could cause harm. The subspecialty of allergy began with the coining of the term by Von Pirquet in 1906 to describe disorders resulting from hyper-reaction to normally innocuous environmental agents. Understanding the scientific basis of the immune system and allergy allowed Noon and Freeman, and later Cooke, to develop allergen immunotherapy. Initially the technique was crude, but with the subsequent key discovery of IgE, more accurate methods of diagnosis (such as the radioallergosorbent test (RAST)) and treatment ensued. The efficacy of specific immunotherapy has been demonstrated by many double-blind trials culminating in the WHO position paper. DNA recombinant technology has provided detailed molecular understanding of allergic disorders, which has resulted in several novel methods of immunotherapy that are potentially safer and more effective. Use of recombinant allergens, T-cell peptides, DNA vaccination with CpG motifs or plasmid vectors and anti-IgE strategies with monoclonal antibodies are showing promise.

How long does the effect of birch pollen injection SIT on apple allergy last?

Recent studies showed that injection specific immunotherapy (SIT) with birch pollen extract greatly reduces or cures the associated apple allergy in a large proportion of birch pollen-allergic patients. However, the long-term efficacy of SIT for apple allergy has not been assessed. To evaluate the duration of the effect of injection SIT with birch pollen extract on apple allergy in birch pollen-allergic patients. Thirty birch pollen-allergic patients showing both the clinical disappearance of apple allergy and a negative SPT with fresh apple at the end of their injection SIT course were followed-up at 12-month intervals from 6 months after SIT was stopped. Apple tolerance as well as SPT was assessed on all occasions. Fifty-seven birch pollen-allergic subjects without apple allergy and not submitted to SIT regularly followed-up for the onset of oral allergy syndrome (OAS) were used as controls. The overall prevalence of OAS after 30 months of follow-up did not differ between patients and controls. Although most patients became re-sensitized to apple by SPT over time, >50% of them were still able to tolerate eating the fruit at the 30-month follow-up visit. Although most patients show a 'natural', gradual propensity to apple re-sensitization (a consequence of prolonged and repeated inhalation of birch pollen responsible for primary sensitization?), the clinical effects of injection SIT on food allergy seem rather long lasting.

T-cell cytokine pattern at three time points during specific immunotherapy for mite-sensitive asthma.

Several lines of evidence indicate that specific immunotherapy may act by modifying the patterns of cytokines produced by helper T cells. However, different protocols have been used and different results obtained. To quantify the effect of specific immunotherapy on the TH1/TH2 T-cell cytokine pattern at the single cell level. We examined the interferon-gamma/interleukin-4 ratio in peripheral blood CD4+ and CD8+ T cells from 12 subjects with house dust mite-sensitive asthma using a flow cytometric method of intracellular cytokine detection. Cytokine production was determined following stimulation with phorbol myristate acetate/ionomycin, a policlonal activator. Subjects were examined at three occasions: before specific immunotherapy, after the 3-months dose increase phase and after 1 year of treatment. During the treatment year patients kept a diary in which they recorded: (a) symptoms of asthma according to a 0-3 grading (0 = absent, 1 = mild, 2 = moderate, 3 = severe); (b) number of puffs (100 microg) per day of salbutamol required to control symptoms; and (c) peak expiratory flow. Specific immunotherapy improved clinical indices of disease activity including symptom scores and medication use during the treatment year, and had a marked effect in increasing the interferon-gamma/interleukin-4 ratio in peripheral blood CD4+ T cells already after the dose increase phase (5.47 +/- 1.5 vs 4.07 +/- 1.49%, P = 0.03) with and a further rise after 1 year's treatment (16.12 +/- 2.8 vs 4.07 +/- 1.49 and 16.12 +/- 2.8 vs 5.47 +/- 1.5%, P = 0.001 and P = 0.002, respectively). There were no significant changes in the interferon-gamma/interleukin-4 ratio in peripheral blood CD8+ T cells at the three times of the study. These data add to view that the efficacy of specific immunotherapy may be attributed to a modified cytokine secretion of CD4+ T cells.

Mechanisms of allergen specific immunotherapy

Summary Clinical efficacy of specific immunotherapy (SIT) in the treatment of respiratory allergic diseases as well as venom allergy has been demonstrated in various well-controlled studies. However the precise mechanisms of SIT have not been well defined, and for more than twenty years now, research on immunological markers of efficacy of SIT raised many theories on the mechanism of SIT. Recently, the use of molecular genetic techniques constituted a «breakthrough in the comprehension of the immunomodulatory effects of SITsince it has been demonstrated clearly that SIT induces a shift in the Th2/ Th1 balance. At the first stage there is a desensitization of effector cells like basophils, mast cells and eosinophils leading to a reduction of inflammatory mediators release. Simultaneously T lymphocytes and antigen-presenting cells are committed to the production of Th1-type cytokines although Th2-type cytokines are damped. This result in the modification of allergen-specific IgE and IgG4 production pattern and an inhibition of effector-cells migration and activation.

Clinical efficacy of specific immunotherapy to cat dander: a double-blind placebo-controlled trial

Clinical efficacy of specific immunotherapy to cat dander: a double-blind placebo-controlled trial

Specific Immunotherapy Suppresses IL-1β and IL-8 Levels in Nasal Secretions: A Possible Explanation for the Inhibition of Inflammatory Cell Migration

The efficacy of specific immunotherapy in the treatment of allergic rhinitis is now clearly established. The fundamental principle of this form of therapy is still not fully understood, although considerable advances have been made in clarifying various aspects of the mechanisms of action. An important effect of the therapy is the inhibition of migration of inflammatory cells into the mucosa. The results of in vitro investigations and characterization of the cytokine profiles in biopsy specimens from skin and nasal mucosa at the time of an allergeninduced late-phase reaction support the view that reorientation of a Th2 lymphocyte immune response in the direction of a Thl reaction is a fundamental aspect of the mechanisms of the immunotherapy. In order to further clarify the reasons for the cellular infiltration and to obtain evidence for the postulated Th2/Th1 switch in the nasal mucosa, we have measured various cytokines in the nasal secretions from 34 grass-allergic patients participating in a randomized double-blind, placebo-controlled study of specific immunotherapy. One group of 17 patients was treated with a grass pollen allergoid preparation (Allergovit&#174;), whilst the other group received a histamine-containing placebo. Cytokine determinations were performed using enzyme-linked immunosorbent assays with nasal lavage samples obtained before the beginning of therapy and at three time points during the pollen season. Interleukins (IL) 4 and 5 are typical Th2 cytokines effecting the stimulation of IgE synthesis and the activation and differentiation of eosinophil granulocytes, respectively, but they were not detectable in significant amounts in the nasal secretions. Therefore, the investigation did not provide evidence for a T helper cell switch. IL-1&#914;, IL-6, and IL-8 were consistently detectable. Specific immunotherapy had no effect on the nonspecific proinflammatory cytokine IL-6. There were significant reductions in the concentrations of the chemokine IL-8 (p &#60; 0.05) and the important proinflammatory cytokine IL-1&#914; (p &#60; 0.005) in nasal secretions from the treatment group during the pollen season, but not in the placebo group. These two cytokines play an important role in transendothelial cell migration, and their reduced concentrations as a result of the specific immunotherapy may contribute at least in part to the inhibition of inflammatory cell migration into the nasal mucosa. These observations are in keeping with the anti-inflammatory effect of the specific immunotherapy.

Specific immunotherapy in house dust mite allergy.

Specific immunotherapy (SIT) was introduced in 1911 (1) and for many years remained based on empiricism. Extracts of unknown quality and shelf-life (e.g., house dust, Candida albicans, bacteria) were used and the efficacy of SIT was seriously questioned. The introduction of standardized extracts made it possible to increase the efficacy of immunotherapy and double-blind placebo-controlled studies have demonstrated the efficacy of this form of therapy in rhinitis, asthma, and conjunctivitis. The increased efficacy of immunotherapy was associated with an increased risk of anaphylactic reactions (2-4), leading again to question the future of SIT (5). International guidelines have been issued to improve the use of SIT (6-8). SIT is the only treatment intervention that may alter the course of allergic diseases and new methods of specific and nonspecific immunotherapy are being proposed and may prove to be efficacious and safe (9). SIT is still widely used throughout the world. In the future several approaches may be interesting, but all of them are based on the perfect characterization of allergenic molecules and epitopes causing the IgE-mediated immune response. New technologies using molecular biology and genetic engineering have made significant progress in the characterization and preparation of allergens.

Specific immunotherapy reduces the antigen-dependent production of eosinophil chemotactic activity from mononuclear cells in patients with atopic asthma

Background: The efficacy of specific immunotherapy has been verified. There is accumulating evidence focusing on the T lymphocyte-eosinophil interaction in the pathogenesis of asthma. The aim of this study was to clarify whether immunotherapy affects the production of eosinophil chemotactic activity (ECA) from peripheral blood mononuclear cells (PBMC). Methods: PBMC obtained from persons with bronchial asthma who were sensitive to Dermatophagoides farinae (Df) or from healthy volunteers were cultured for 96 hours in the presence or absence of Df. ECA in culture supernatants was assayed by means of the modified Boyden's chamber method. Results: There was no significant difference in the baseline levels of ECA between asthmatic persons treated with immunotherapy and those without immunotherapy. The addition of Df (10 to 104 ng/ml) enhanced the ECA production in a dose-dependent fashion in asthmatic persons without immunotherapy, and there was a statistically significant correlation between the concentrations of Df and the levels of ECA (rk = 0.34; p < 0.05). In contrast, Df-dependent ECA production was suppressed in asthmatic persons with immunotherapy, and the suppressive effect was observed from 4 weeks after rush immunotherapy. Conclusions: These results indicate that immunotherapy induces the suppression of antigen-dependent production of ECA from PBMC. This may contribute to the attenuation of eosinophil infiltration into the airways in asthma patients. (J ALLERGYCLINIMMUNOL1994;94;160-6.)

Specific immunotherapy reduces the antigen-dependent production of eosinophil chemotactic activity from mononuclear cells in patients with atopic asthma.

The efficacy of specific immunotherapy has been verified. There is accumulating evidence focusing on the T lymphocyte-eosinophil interaction in the pathogenesis of asthma. The aim of this study was to clarify whether immunotherapy affects the production of eosinophil chemotactic activity (ECA) from peripheral blood mononuclear cells (PBMC). PBMC obtained from persons with bronchial asthma who were sensitive to Dermatophagoides farinae (Df) or from healthy volunteers were cultured for 96 hours in the presence or absence of Df. ECA in culture supernatants was assayed by means of the modified Boyden's chamber method. There was no significant difference in the baseline levels of ECA between asthmatic persons treated with immunotherapy and those without immunotherapy. The addition of Df (10 to 10(4) ng/ml) enhanced the ECA production in a dose-dependent fashion in asthmatic persons without immunotherapy, and there was a statistically significant correlation between the concentrations of Df and the levels of ECA (rk = 0.34; p < 0.05). In contrast, Df-dependent ECA production was suppressed in asthmatic persons with immunotherapy, and the suppressive effect was observed from 4 weeks after rush immunotherapy. These results indicate that immunotherapy induces the suppression of antigen-dependent production of ECA from PBMC. This may contribute to the attenuation of eosinophil infiltration into the airways in asthma patients.

Spontaneous histamine release in whole blood in patients before and after 4 months of specific immunotherapy.

Spontaneous histamine release (SHR) in whole blood was assessed before and after 4 months of specific immunotherapy (SIT) for allergic rhinoconjunctivitis in 32 patients. Spontaneous histamine release was significantly enhanced (P < 0.05) in patients prior to immunotherapy compared with 20 controls. Spontaneous histamine release decreased significantly in patients after 4 months of specific immunotherapy (P < 0.04) and almost reached the same values as spontaneous histamine release in controls. Clinical success of treatment after 4 months was seen in 15 patients (improvement > or =50%), 10 of whom showed a significant decrease in spontaneous histamine release. Decrease of spontaneous histamine release after 4 months indicates the efficacy of specific immunotherapy already at an early stage of treatment. Assessment of spontaneous histamine release appears to be a useful and easily performable method for monitoring success of treatment of patients during specific immunotherapy.