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Immunomodulation - A Cure for Allergic Disease?

Immunotherapy and the Course of Asthma

Jean Bousquet
Hopital Arnaud de Velleneuve
Montpellier Cedex, France

Abstract
Primary and secondary prevention of allergy and asthma by therapeutic allergen vaccines

Jean Bousquet, Antonio M Vignola

Clinique des Maladies Respiratoires, University Hospital, Montpellier, France
And Istituto di Fisiopatologia Respiratoria, Palermo, Italy

Introduction
Although pharmacological intervention to treat established asthma is highly effective in controlling symptoms and improving quality of life, no therapeutic strategy has been demonstrated to cure the condition and very few have modified the natural course of the disease. This must inevitably focus attention on prevention as the ideal approach for the treatment of chronic lifelong and usually incurable disease.

Three levels of prevention can be considered (1).

Primary prevention should be introduced before any evidence of sensitization to factors that might subsequently induce disease. As there is increasing evidence that allergic sensitization which is the most common pre-cursor to the development of asthma can occur ante-natally (2), much of the focus of primary prevention will be on peri-natal interventions but there is very little information concerning allergen vaccination.

Secondary prevention is employed after primary sensitization to allergen has occurred, but before there is any evidence of disease. This will often focus very specifically on the first years of life. Although this is not specifically stated in the WHO document, the secondary prevention of allergy may also refer to the prevention of new sensitizations in a patient already sensitized to other allergens. Secondary prevention of asthma may be attempted in occupational rhinitis, and using allergen vaccination or pharmacotherapy (3, 4) in patients with rhinitis or children with non-asthmatic allergic conditions.

Tertiary prevention involves avoidance of allergens and nonspecific triggers when asthma (and allergic diseases) is established. It is considered that tertiary prevention should be introduced when the first signs of asthma have occurred. However, increasing evidence would suggest that the histopathology of the disease is fully established by the time asthma symptoms occur.

1. Primary prevention of allergy using allergen vaccination:

The immune status and allergen exposure of the mother may influence the immune response in the offspring after birth and may contribute to the primary prevention of allergy. This has been shown in animals' studies.

A prolonged suppression of egg-albumin specific IgE responsiveness was found in the progeny of immunized female rats (5), and an identical effect was produced by the administration of small amounts of specific IgG during the first few days of life. Both manipulations also elevated the primary IgG response to a subsequent immunization (6). Feeding antigen to the progeny of (IgG-transmitting) immune mothers showed that passive and active immunity in the young rat were both suppressing IgE-responsiveness (7). Preconception maternal immunization to dust mite inhibits the type I hypersensitivity response of offspring as shown in female A/Sn mice immunized or not with D pteronyssinus and mated with male C57BL/6 mice (8). Allergen immunization of NIH/OlaHsd females mothers during pregnancy and postpartum significantly reduced the IgE response in the progenies, whereas the IgG2a response to the same allergen was increased. Allergen immunization of the mother 3 days into pregnancy resulted in a significantly lower IgE response in offspring compared with the response in offspring of non-immunized mothers and in offspring of mothers immunized 17 days into pregnancy (9). IgE suppression is detectable in the offspring during the first 4 months of life, but not thereafter and not in the dams (10). However, when the initial immunization at an age of 3 or 4 months was followed by further application of both allergens via their respective routes, IgE suppression persisted up to an age of more than one year. In ovalbumin-sensitized BALB/c mice Th-2/Th-0 immunity present during pregnancy has a decisive impact on shaping the Th-1/Th-2 T cell profile in response to postnatal allergen exposure (11).

If applicable to man, these findings may allow the development of a new strategy for the prevention of allergy and asthma by maternally transferred or neonatally injected allergen-specific monoclonal antiblides in combination with natural or prophylactic exposure to the respective allergens during early childhood or immunization of allergic mothers.

Effect of maternal allergen vaccination on immediate skin test reactivity, specific rye I IgG and IgE antibody was studied in 14 children allergic to grass pollens (12). Fourteen additional children from the same allergic mothers, in whom vaccination was not given during the pregnancy, served as controls. Levels of rye I IgG and total IgE were lower in the sera of children born to mothers who received allergen vaccine (not statistically significant) than their control cohorts. Paired cord blood and maternal blood samples drawn at delivery showed similar levels of rye I IgG, indicating that they freely crosses the placenta. This study suggests that allergen vaccination during pregnancy may have an inhibitory effect on immediate skin reactivity to grass allergens in some of the offsprings. Whether tolerance to other allergens can be induced in children by maternal vaccination remains to be determined.

2. Secondary prevention of asthma using allergen vaccination:

Although drugs are highly effective and usually without important side-effects, they only represent a symptomatic treatment, while allergen vaccination is the only treatment that may alter the natural course of the disease (13-15).

Long-term efficacy of allergen vaccination after it has been stopped has been shown for sub-cutaneous vaccination (16-20). However, in the study of Naclerio et al (19), one year after discontinuation of ragweed immunotherapy, nasal challenges showed partial recrudescence of mediator responses even though reports during the season appeared to indicate continued suppression of symptoms.

Allergen vaccination has been used for the curative treatment of allergic diseases but there are some suggestions indicating that allergen vaccination may have a preventive efficacy. Allergic sensitization begins usually early in life and symptoms often start within the first decade. It has been shown that allergen vaccination was less effective in older patients than in children and that inflammation and remodelling of the airways in asthma are of poor prognosis for an effective allergen vaccination. Moreover, if allergen vaccination is used as a preventive treatment it should be started as soon as allergy has been diagnosed (21).

When allergen vaccination is introduced to patients with only allergic rhino-conjunctivitis, it may stop the development of asthma. The early study of Johnstone and Dutton (22) with several different allergens showed that children receiving allergen vaccination developed asthma in 28% compared to placebo-treated children, who had asthma in 78%. To answer the question” does allergen vaccination stop the development of asthma” the Preventive Allergy Treatment (PAT) study has been started in children, aged from 7 to 13 (23). This study was performed as a multi-center study in Austria , Denmark , Finland , Germany and Sweden in 205 children aged 6 to 14 years. After three years of allergen vaccination, a significantly greater number of children in the control group developed asthma as compared to the active group (Figure 1)24). Before the start of vaccination, 20% of the children had mild asthma symptoms during the pollen season(s). Among those without asthma, the actively treated children had significantly fewer asthma symptoms after 3 years as evaluated by clinical diagnosis (odds ratio, 2.52; p<0.05). Methacholine bronchial provocation test results improved significant in the active group (p<0.05).

Long-lasting effect of sublingual immunotherapy (SLIT) in children with asthma due to house dust mite was examined a 10-year prospective parallel group controlled study (24). 35 underwent a 4- to 5-year course of SLIT with standardized extract and 25 received only drug therapy. The patients were evaluated at three time points (baseline, end of SLIT and 4 to 5 years after SLIT discontinuation) regarding presence of asthma, use of anti-asthma drugs, skin prick tests and specific IgE. in the SLIT group there was a significant difference vs. baseline for the presence of asthma (p=0.001) and the use of asthma medications (p=0.01), whereas no difference was observed in the control group. The mean peak expiratory flow result was significantly higher in the active group than in the control group after 10 years. Sublingual immunotherapy is effective in children and that it maintains the clinical efficacy for 4 to 5 years after discontinuation.

3. Secondary prevention of new sensitizations using allergen vaccination:

Several longitudinal studies report that allergic sensitization increases with age from childhood to adulthood. A study found that monosensitized children are likely to become polysensitized and house dust mite (HDM) sensitization and, at a lower degree, pollen sensitization, apparently seem to play a "triggering" role in the development of polysensitization, since a high proportion of children originally monosensitized to HDM or to pollens became polysensitized (25).

A first study was designed to determine whether allergen vaccination with standardized allergen extracts could prevent the development of new sensitizations over a 3-year follow-up survey (26). 22 children monosensitized to HDM who were receiving SIT with standardized allergen extracts were compared with 22 other age-matched control subjects who were monosensitized to HDM (Figure 3). The initial investigation included a full clinical history, skin tests with a panel of standardized allergens, and the measurement of allergen-specific IgE, depending on the results of skin tests. Children were followed up on an annual basis for 3 years, and the development of new sensitizations in each group was record37) ed. Ten of 22 children monosensitized to HDM who were receiving allergen vaccination did not have new sensitivities compared with zero of 22 children in the control group (p=0.001). This study suggested that allergen vaccination in children monosensitized to HDM alters the natural course of allergy in preventing the development of new sensitizations.

A second study was carried out to increase our knowledge of the ability of allergen vaccination to the onset of new sensitizations in monosensitized subjects (27). 134 children (age range 5-8 years), who had intermittent asthma with or without rhinitis, with single sensitization to mite allergen (skin prick test and serum-specific IgE), were enrolled. Allergen vaccination was proposed to all the children's parents, but was accepted by only 75 of them (SIT Group). The remaining 63 children were treated with medication only, and were considered the Control Group. Injective immunotherapy with mite mix was administered to the SIT Group during the first three years and all patients were followed for a total of 6 years. All patients were checked for allergic sensitization(s) by skin prick test and serum-specific IgE every year until the end of the follow-up period. Both groups were comparable in terms of age, sex and disease characteristics. 123 children completed the follow-up study. At the end of the study, 52 out of 69 children (75.4%) in the SIT Group showed no new sensitization, compared to 18 out of 54 children (33.3%) in the Control Group (p<0.0002). Parietaria , grass and olive pollens were the most common allergens responsible for the new sensitization(s). The conclusions of the study propose that allergen vaccination may prevent the onset of new sensitizations in children with respiratory symptoms monosensitized to HDM.

A retrospective study was conducted conducted in order to assess the prevention of new sensitizations in monosensitized subjects treated with allergen vaccination vs. monosensitized patients treated with anti-allergic drugs (28). 8396 monosensitized patients with respiratory symptoms were selected according to an open, retrospective design. Group A included 7182 patients submitted to allergen vaccination (and anti-allergic drugs when needed) for 4 years and then treated with drugs for at least 3 years. Group B included 1214 patients treated only with drugs for at least 7 years. All patients underwent prick test with a standard panel of allergens and total and specific IgE determination before and after 4 years of treatment and again 3 years later. Groups were well balanced. Polysensitized subjects were 23.75% in Group A and 68.03% in Group B after 4 years (p<0.0001) and 26.95% and 76.77%, respectively, after 7 years (P < 0.0001). Asthmatic subjects were more prone to develop polysensitization in comparison to subjects suffering only from rhinitis (32.14% instead of 27.29% after 4 years, 36.5% instead of 31.33% after 7 years; p< 0.0001). Specific IgE decreased by 24.11% in Group A and increased by 23.87% in Group B (p<0.0001). Total IgE decreased by 17.53% in Group A and increased by 13.71% in Group B (p<0.0001).

In a fourth study, preseasonal grass pollen immunotherapy was administered for three years in children and the group of patients was examined six years after discontinuation of treatment (29). Thirteen patients with previous allergen vaccination and 10 patients of the control group were prospectively followed. During the observation time, scores for overall hayfever symptoms (p<0.004) and individual symptoms for eyes (P < 0.02), nose (p<0.04) and chest (p<0.01) as well as combined symptom and medication scores (p<0.002) remained lower in the group with previous allergen vaccination. Only 23% of patients with previous pollen-asthma who had received allergen vaccination experienced pollen-associated lower respiratory tract symptoms compared to 70% in the control group (p<0.05). Eight years after commencement of allergen vaccination, 61% of the initially pollen-monosensitized children had developed new sensitization to perennial allergens compared to 100% in the control group (p<0.05). This study confirmed that allergen vaccination in children with pollen-allergy reduces onset of new sensitization and therefore has the potential to modify the natural course of allergic disease.

There is now sufficient evidence to support the effect of allergen vaccination in the prevention of new sensitizations in children with mono- or pauci-sensitizations. The mechanisms underlying these findings are still unclear but may be related to the effect of immunotherapy in the Th1-Th2 balance (30, 31). The reduction of allergen-specific Th2 response may be involved in a more general activation of Th2 cells which are globally increased in atopic subjects (32) thereby inducing a Th1-driven response after allergen stimulation (33).

Conclusions
In the future, allergen vaccination may be used in the secondary prevention of asthma (34). Allergen vaccination is the only treatment that may alter the natural course of allergic diseases (20). Allergen vaccination with pollen extracts in children with rhinitis prevents the onset of persistent asthma (23) (Figure 4). Moreover, allergen vaccination in mono-sensitized young children was found to reduce the onset of new sensitizations. More studies are however needed to determine how allergen vaccination may modify the allergic disease or impair progression to asthma

It is therefore proposed that allergen vaccination should be started early in the disease process in order to modify the spontaneous long term progress of the allergic inflammation and disease (13, 35, 36).

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