Different methods of local allergen‐specific immunotherapy

In the treatment of allergic disorders, specific immunotherapy (SIT) occupies a central role as the only currently available causal method of treatment. The concept of “local immunotherapy” includes all nonsubcutaneous forms of SIT, which are used to treat allergic disorders such as rhinitis and asthma. Nasal, bronchial, oral and sublingual administration of allergen extracts is regarded as local immunotherapy (LIT). Attempts were made very early to produce tolerance to certain allergens by the oral route. Dakin reported in1829 that North American Indians regularly chewed small amounts of leaves of the “poison ivy” (Rhus toxicodendron) in order to prevent or weaken the severe dermatitides that occur after contact with this plant (Dakin, 1829 quoted after (1)). In 1900, 11 years before the first work on subcutaneous immunotherapy, Curtis published an article about the efficacy of oral allergen-specific immunotherapy (OIT) in hay fever (2). This was followed five years later by other reports about the success of OIT in cow's milk allergy (3). In the 1920s and 1930s, too, reports of positive experiences with this method appeared again and again. However, a negative, multicentre comparative study of ragweed pollinosis (4) (in which, interestingly, good results were reported in children!) severely limited the use of OIT in adults in the Anglo-Saxon countries. In the early 1950s, Schuppli in Basel, Switzerland took up OIT again. His positive results in children ensured that this method soon became widespread 5-12). New methods of local application were sought, because various studies in recent years showed that OIT is clearly inferior to allergen-specific subcutaneous (injected) immunotherapy (SIT) with regard to both clinical and immunological efficacy. From a clinical aspect however, there is a whole series of arguments to explain the preference for LIT compared to injected IT. Poor compliance can limit the applicability of injected SIT (13). Because LIT can be carried out at home by the patient and the injections in the doctor's office are no longer necessary, greater compliance is ascribed to LIT than to SIT. However, more precise studies of this subject are lacking, so the effective compliance of LIT patients is not known. Severe systemic side-effects restrict the broad use of SIT, although the risk in hay fever patients is lower compared to asthma patients (14, 15). When SIT is carried out correctly, severe systemic side-effects in patients with allergic rhinitis, who are treated with potent extracts, occur in about 5% of all the SIT injections (16). Based on the published data, on the other hand, systemic side-effects appear to occur only very rarely with LIT. The rapid development of molecular biology and progress not only in general allergen characterization but also in the production of large quantities of recombinant allergens have reawakened interest in recent years in local immunotherapy (LIT), both in science and among the producers of allergen extracts. At present there appears to be a trend away from oral towards sublingual allergen-specific IT (SLIT). Experimental evidence for the local administration of allergen extracts to the mucous membranes of the respiratory tract is based on the model of local induction of tolerance 17-20). The concept of oral and sublingual IT derives from animal studies, which show that tolerance can be produced by taking in antigen orally 21-23). Hypothetically, the effect of sublingual IT can be explained by several mechanisms. The oral mucosa is especially rich in dendritic cells, which are known to demonstrate strong MHC class II molecule expression (24). These dendritic cells can absorb and process allergens and antigens and also activate autologous native T lymphocytes (25). Animal models in which induction of tolerance in the oral mucosa was investigated show that the dendritic cells of the oral mucosa can act as antigen-presenting cells, and that the clonal anergy of specific T cells is one of the mechanisms by which tolerance can be induced through the oral mucosa (26, 27). In addition, dendritic cells produce IL-12, which favors the development of Th1 cells compared to that of Th2 cells (28, 29). Three important aspects are emphasised below through detailed descriptions, to give a better understanding of the immunological reactions after oral administration of an allergen: the absorption of an allergen through the intact mucosa; the resulting induced mucosa-associated immune reaction; the possibility of influencing existing sensitization by oral administration of an allergen. Since the observations of Herbst in 1834, it has been known that corpuscular elements such as starch grains, pollens and spores can be absorbed through the intact mucosa under physiological conditions (12, 30, 31). Besides these corpuscular elements, macromolecules and proteins are absorbed in biologically and immunologically active forms 32-38). It is important to emphasize that macromolecules of a certain, allergologically relevant size can pass the mucosa much more easily in atopic subjects than in healthy persons 39-42). It is thus certain that under physiological circumstances allergens also can be absorbed in an immunologically active form and in substantial quantities through the mucosa. The degree of permeability is influenced by both exogenous (infections, medications, e.g. acetylsalicylic acid, nonsteroidal anti-inflammatory drugs (NSAID) and others) and endogenous factors (atopic disposition, immunological reactions such as formation of a complex between allergen and serum IgA) (43). These characteristics, described for the intestinal mucosa, apply also by extension to other mucous membranes, for instance to the oral and nasal mucosa or the mucous membranes of the respiratory and urogenital tract. The submucosa contains scattered collections of lymphatic tissue of T and B lymphocytes, which are concentrated in the intestine in Peyer's plaques and belong together with other immunoreactive cells to the MALT (mucosa-associated lymphoid tissue). The abbreviation GALT (gut-associated lymphoid tissue) is also used in connection with the digestive tract. Active exchange of lymphocytes takes place in this nonencapsulated lymphatic tissue, with migration especially into the submucosa of other mucous membranes 44-47). An immune reaction can spread into other MALT sites by means of migration of locally activated T cells without antigen getting into the circulation and without changes of immunological parameters being detectable in the serum 48-50). However, local administration of antigen appears to lead to an immune reaction in the entire MALT only if as many Peyer's plaques or similar structures (e.g. in the respiratory tract) are included by the antigen contact (51). This could explain, for instance, why nasal IT has a local effect on the symptoms of rhinitis but is unable to influence asthma symptoms (52), and why the sublingual application form followed by spitting out the extract (so-called sublingual-spit method) gives less satisfactory results than sublingual hyposensitization followed by swallowing of the allergen extract (sublingual-swallow method). Wells and Osborne observed in 1911 that guinea pigs could no longer be sensitized parenterally to zein (a maize protein) if they were fed with maize beforehand (32). Some time later, Sulzberger (53) and Chase (54) showed that animals could no longer be sensitized epicutaneously if the antigen was given orally beforehand. This proves that specific tolerance can be induced orally. It would be desirable to exploit this possibility of inducing tolerance with local IT. However, since LIT is performed in an already sensitized body, those observations showing that existing sensitization can be weakened or even made to disappear by oral administration of the allergen are important (49, 55). It is important that, unlike parenteral administration, oral administration of an antigen is more likely to suppress the specific humoral immune response. This would explain why changes in the serum immunoglobulins are generally not observed with OIT, and in particular there is no rise in so-called blocking IgG (56). The degree of tolerance achieved by oral administration of an antigen is not only genetic but also determined by numerous other complex interactions (57, 58), where age, the current permeability of the intestinal mucosa, the dose of allergen, the allergen quality, the form of administration, and the intervals between allergen doses, play a crucial part 59-65). On the basis of more recent research results, allergen-specific subcutaneous immunotherapy appears to cause a shift of the immune response of the activated T cells from a T helper type 2 cytokine profile (interleukin-4 and interleukin-5) to a T helper type 1 cytokine profile (interleukin-2 and interferon-γ) (66). In contrast, local mechanisms such as the production of specific secretory IgA antibodies and the production of specific T suppressor cells play an important part in LIT (67). Although many changes during immunotherapy can be explained by these mechanisms, by no means all of the questions about the mode of action of immunotherapy have been answered yet. Indisputably, the progress in molecular biology in recent years will allow new treatment strategies in mucosa-associated forms of allergy, which will go far beyond what has been achieved so far. All of the studies considered had to meet the following criteria: (a) Placebo-controlled, double-blind study design (DBPC studies). (b) Defined allergen extracts and dosages. (c) Appropriate treatment protocols and statistics with sufficiently large numbers of patients (> 7 patients per group). (d) Publication in peer-reviewed journals in English. (e) Symptom/medication score present. Pollen extracts (birch, grasses, pellitory (Parietaria) and ragweed (Ambrosia)) were used in most LIT studies. House dust mites and cat extracts have been investigated less well until now. The extracts are derived from different manufacturers and are standardized with different methods. Validation of the extract quality was not carried out, but it can be assumed that the manufacturers have followed the international guidelines for allergen standardization and manufacture (68). Both aqueous and powdered extracts are used in local and bronchial IT. Besides nonmodified extracts, allergoids are also employed. Both aqueous extracts and gastric acid-resistant capsules are used in oral IT. In contrast, aqueous extracts were used exclusively in all sublingual studies. Because the potency of the extracts was given in the manufacturer's arbitrary units in most studies, a direct comparison of dosage is not possible. Many of the studies cited here were performed only over a short period, a few weeks to a few months, pre- or co-seasonally. The treatment period was over one year in only five studies. The duration of treatment was not included in assessing clinical efficacy, although it was shown with injected IT that the success of treatment depends on the duration of the IT (14). The degree of clinical success was dependent on the duration of the IT in only one oral IT study (69). However, it is important to emphasize here too, that when an extract is ineffective in a short-term study, clinically relevant efficacy does not automatically follow when it is given for a prolonged period. Nasal IT can be given both preseasonally and perennially. The allergens are self-administered by the patient, either in powder form or as an aqueous extract (solution). During administration of the allergen, the patient exhales or vocalises in order to avoid bronchial deposition of allergen. The extracts are taken daily or on alternate days during the induction phase and then weekly during the maintenance phase. The clinical efficacy of nasal IT was assessed on the basis of 17 studies 70-87). Sixteen of 17 studies show statistically significant clinical efficacy. Overall, 419 patients were treated in these 17 studies, and 22 patients in the “no-effect” study (83). The patients were reviewed after two years in only one study. No long-term effect was found after stopping the nasal IT, so that nasal IT can be recommended currently only as preseasonal prophylactic treatment for pollen-induced rhinitis (85). No severe systemic side-effects in the studies. However, the of the patients had local symptoms such as and Nasal IT can In one study, patients had to be from the active because of However, local side-effects with the in patients who either or allergen have nasal IT of inducing local symptoms for a prolonged period during the dose phase and during the However, this to be of because the in the treated patient not lead to a which that the patients these symptoms and not to more because of In the local side-effects induced by the nasal IT were and of short in the nasal was found in many studies The reactions not appear to be influenced by nasal IT In most of the studies, there were no relevant changes in the allergen-specific IgG in the in one study there was a rise in allergen-specific IgG and IgA in the serum and nasal In study, there were serum in the treated compared to in the during the a significant in the positive cells and a in the after nasal However, these changes were not by changes in the serum IgG or Nasal immunotherapy the symptoms in patients with allergic rhinitis in of 17 studies. efficacy was found for the following ragweed and dust mites in two studies The efficacy and were investigated in patients also in only one study (83). The side-effects not appear to a relevant in nasal immunotherapy and can be under well with local or The patients were reviewed after two years in only one study. No long-term effect was found after stopping the nasal IT, so that nasal IT can currently be recommended only as preseasonal prophylactic treatment for pollen-induced rhinitis (85). The clinical efficacy of bronchial immunotherapy was investigated in two studies allergens efficacy with of the and score was during a treatment period in one study was induced in the of patients in both studies. In most the in was to less than of the but in a few patients a reaction less than of the was No other systemic reactions with bronchial IT. In the only study that showed a clinical no significant in was observed between the active and the On the other hand, there was a significant in bronchial allergen tolerance in the treated In contrast, the reactions was a significant rise in and but no in allergen-specific and during the in one study these parameters were in the other study IT has been for clinical is a substantial risk of severe and The efficacy of oral IT was studies of these studies showed no efficacy. in the was observed in studies (birch, ragweed dust In a study gastric acid-resistant ragweed a significant in the and was in of patients who the allergen dose (> In study, the only significant between the treated and was a in the symptoms in the treated Because no were found in this study with regard to nasal symptoms and the of oral IT be regarded as with regard to and patient allergen had to be In to a study with in gastric acid-resistant capsules no efficacy The for the of oral IT with be to in the of these since both allergens are very in the In the only study which showed a significant in symptoms after two a five dose of an aqueous dust extract was used than in subcutaneous IT for years in children (69). The positive of a prolonged duration of treatment were in the in the and were no changes in the rhinitis symptoms during the first year of treatment the rhinitis in the and The asthma symptoms only in the patients were treated in the and patients in the studies. administration of allergen can systemic which can be with rhinitis and one with asthma were in a study of 22 However, the was the as in the of were observed in study patients and in study with patients there was one of In oral IT study with cat two patients had severe which however, not to the treatment side-effects in one study in which very were used that were the dose used in subcutaneous IT In most studies, no changes were found in the nasal and However, there was a in the nasal in one study and two other studies found an in the significant rise in allergen-specific was observed only one after the of the oral IT, with a of the rise in In addition, the allergen-specific IgG not the IgA) in the treated rise in and was also observed during the treatment in a study with allergens and in two studies with ragweed However, this could not be in other studies IT has been for clinical efficacy in was found in only of studies, and this was for allergens in gastric acid-resistant dust mites after treatment for at one and immunotherapy can be given in two different either where the extract is in the for absorption through the oral mucous membranes and is then out or administration, where the extract is after a certain time in the of efficacy is ascribed only to the method in the current on specific immunotherapy IT is carried out either or perennially. The patients the allergen extracts at as aqueous either daily or two days in the induction and one to a during the maintenance treatment. In studies with the sublingual-spit method clinical efficacy was found for cat allergens and for dust mites in children was for sublingual IT with the method for extracts of dust mites and with and asthma of patients were treated with these allergens in studies. No systemic side-effects have been reported so far in and in most of the studies no were found between the treated and the the of systemic The most side-effects are local with in the and oral followed by symptoms In a study children and there were of systemic side-effects patients with 11 patients with asthma of and patients with In study in in one patient In a published of the of immunotherapy there were no severe or even reactions in the studies. was an of local side-effects in adults and children In one study, there was a significant in the and a in the nasal However, there were no changes in the and bronchial allergen In other studies, a significant was found in the and in the nasal in other studies no changes were found in the investigated parameters The allergen-specific antibodies not appear to be influenced by sublingual IT in a few studies more recent studies found a significant rise in allergen-specific both and together with antibodies IgG antibodies in one study but they the in study significant rise in the IgG was observed for and for the in study there was no in the antibodies sublingual immunotherapy, the and were in all studies for dust mites and five and cat allergens The were five to than in subcutaneous IT and the clinical efficacy was to that of subcutaneous IT. studies were exclusively in children and systemic side-effects more in these studies Overall, however, in the by of studies children and there were similar of exclusively reactions in children and adults The on allergic rhinitis and on has given the studies of the efficacy of sublingual immunotherapy in the treatment of and rhinitis in adults and allergic rhinitis in children the to the of However, this only for immunotherapy in which the dose is at in comparison to the subcutaneous form of The for sublingual IT then to those for the subcutaneous form are a few studies which have compared local with subcutaneous IT In one of these studies, local nasal IT was compared with subcutaneous IT for nasal IT not a in subcutaneous IT was effective In two other studies, the efficacy of bronchial IT was compared to subcutaneous IT of the studies showed that bronchial IT had a greater effect on the in bronchial than injected IT the other study the and subcutaneous IT was compared in studies. In two of these studies, oral IT in children was inferior to subcutaneous IT in study in the effect was about the In a dust study, the efficacy of subcutaneous IT was greater than that of sublingual IT in study, which compared subcutaneous with sublingual IT in patients allergic to better results were with sublingual IT in the In a published study, which compared the efficacy of sublingual and injected IT, there was a in the and compared to the preseasonal phase for both patient this study was not so that of the that the was about the in both it is the clinical in symptoms can be to the treatment. study, which investigated parenterally injected IT followed by or oral IT showed that the treated patients had rhinitis but no in use However, similar study was unable to the efficacy of oral Because only one comparative study with a has been so comparison of these two forms of is In this comparative study, the only one so patients were treated either with IT or with subcutaneous IT for two years with a two patients in the patients in the and patients in the the study. In the two treated a significant in the and was found and there were no significant between the and In the of allergen were used than in the In the there were two severe systemic reactions and only local reactions were observed in the The that be because of the better profile together with clinical efficacy. However, before can be recommended generally as the of SIT, the following be long-term efficacy, efficacy, patient and patient The long-term efficacy of local IT has not been However, since long-term efficacy and aspects are the of injected IT the of local IT, which, subcutaneous SIT, has to be given for several be studies of long-term efficacy and the effect of have been these questions be answered The and treatment of allergic local IT, in the of the of the patients about allergen and prophylactic and when IT is the of a (14). use of local IT without is not because the and side-effects and also the compliance and the long-term efficacy are less well for local IT than for subcutaneous IT. use of local IT results in patient with treatment which in the of the other in allergic the who has been in all treatment methods and and oral IT are currently recommended only in studies because of the of the clinical efficacy and the severe nasal IT have been in adults with allergic rhinitis by allergy and ragweed The efficacy in dust mites was in two studies. for nasal IT are from such symptoms be by who have had systemic side-effects on subcutaneous IT and either show compliance or have subcutaneous IT. However, the risk of inducing asthma during nasal IT a to this form of treatment which is used by the patient without by a The patients be about the and treatment in the of systemic IT has been for dust and cat allergens in studies in patients with rhinitis and asthma. The available are not at present especially for patients with asthma. The the immunotherapy, with a dose at compared to subcutaneous administration, as the degree of evidence for the treatment of and rhinitis in adults and allergic rhinitis in The for follow those for by patients who have a of injections or those with severe side-effects on subcutaneous studies with standardized sublingual extracts to the long-term efficacy and the efficacy and of this in asthma patients children with are in order to the of this form of