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 Table of Contents  
REVIEW ARTICLE
Year : 2012  |  Volume : 26  |  Issue : 2  |  Page : 50-60

Respiratory allergic diseases and therapeutic intervention using allergen-specific immunotherapy


Department of Pulmonary Medicine, V. P. Chest Institute, University of Delhi, Delhi, India

Date of Web Publication27-May-2013

Correspondence Address:
Shailendra N Gaur
Department of Pulmonary Medicine, Vallabhbhai Patel Chest Institute, University of Delhi, Delhi - 110 007
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0972-6691.112548

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  Abstract 

Bronchial asthma and allergic rhinitis are the most common respiratory allergic disease mediated through type-1 immune reaction. The imbalance of TH1 and TH2 cells is responsible for increased immunoglobulin E (IgE) level and release of immune mediators, producing symptoms in the particular genetically predetermined target organ. Pharmacotherapy is effective in controlling the symptoms of allergic diseases, but withdrawal of medication leads to reappearance of symptoms in a short span of time. The therapeutic modality, namely allergen-specific immunotherapy, corrects the TH1 and TH2 imbalance and thus effects the natural course of allergic disease prescribed in addition to the pharmacotherapy. Immunotherapy has also been found to prevent development of newer allergies and progression of rhinitis to asthma. The subcutaneous immunotherapy with perennial subcutaneous injections and stepwise procedure is the standard and established method. Here, the injections are started with a very high dilution of antigen and then slowly increased to the optimal maintenance dose. However, precautions should be taken to take care of the related side-effects, including anaphylaxis. Patient education and use of this therapy only by trained physicians is mandatory, and it should be practiced at a center having facilities for the management of anaphylaxis. There are various trials in the literature to support improvement by immunotherapy. In Indian studies, favourable results were noted in symptom score, skin sensitivity, airway reactivity (PC20), specific immunoglobulin (Ig) E, Ig G1 and Ig G4. Researches are aimed on a safer and more acceptable route of administration of the allergen. The sublingual route for immunotherapy has been used from 1986 and, till today, has been found to be equally effective and safe. Considering the difference in geo-environmental variation in India from the western world, an Indian guideline for practice of allergen immunotherapy was published in 2009, where consideration was given to the Indian environment, pattern of seasons, presence of different/newer allergens, affordability and feasibility of certain tests in the Indian context.

Keywords: Airway reactivity (PC20), allergen, allergen-specific immunotherapy, hypersensitivity


How to cite this article:
Gaur SN. Respiratory allergic diseases and therapeutic intervention using allergen-specific immunotherapy. Indian J Allergy Asthma Immunol 2012;26:50-60

How to cite this URL:
Gaur SN. Respiratory allergic diseases and therapeutic intervention using allergen-specific immunotherapy. Indian J Allergy Asthma Immunol [serial online] 2012 [cited 2017 Mar 23];26:50-60. Available from: http://www.ijaai.in/text.asp?2012/26/2/50/112548


  Introduction Top


The immune system has been designed to protect the integrity of the host by maintaining the healthy "status quo" called homeostasis. The immune response is basically a mechanism used by vertebrates to eradicate infectious agents that succeed in penetrating the natural barriers, and it uses a complex array of protective mechanisms to control and eliminate invading organisms. But, inappropriate immune response to an antigen is harmful to the host and is termed as hypersensitivity or allergy. The term allergy was originally defined as altered reactivity to exogenous antigens, and is now used synonymously with atopy. Allergic reactions can be categorized as "immediate" or "delayed" based on the time taken for symptoms to appear after antigen exposure. There may be "humoral" or "cell mediated" immune response based on the type of components involved.


  Allergic Diseases Top


Allergy represents a major health problem affecting more than 25% of the population worldwide. Allergic patients (type I) are characterized by the increased production of immunoglobulin E (IgE) antibodies against antigens (allergens) from different sources, e.g., pollen, mites, fungi, insects, animal dander and foods. The type I allergy (immediate) leads to allergic manifestations, e.g., allergic rhinitis, asthma, atopic dermatitis, urticaria and anaphylactic shock triggered by allergen-induced cross-linking of effector cell-bound IgE antibodies and the release of inflammatory mediators such as histamine and leukotrienes. [1],[2],[3] Allergic diseases affect an individual in terms of quality of life, work performance and productivity. [4] The prevalence of atopic diseases has increased in many industrialized countries during the past few decades. [5]

Allergic rhinitis

Allergic rhinitis (AR), commonly called "hay fever," is one of the most common atopic diseases affecting 10-25% of the population worldwide. [6] Prevalence of allergic rhinitis has been reported in 7.3% of the Indian children. [7] It is an IgE-mediated inflammation of the nasal mucosa characterized by inflammatory infiltrates containing eosinophils, T cells, mast cells and basophils that release several mediators like chemokines and cytokines on interaction with specific allergens. [8] AR is often associated with conjunctival symptoms. AR also triggers a systemic inflammation, which can augment inflammation in both the upper and the lower airways. Hence, asthma and rhinitis are common co-morbidities suggesting the concept of "one airway, one disease." [9] Epidemiologically, up to 40% of patients with AR have asthma, and up to 80% of patients with asthma experience nasal symptoms. [10]

Asthma

Asthma is one of the most common chronic diseases of the airways characterized by bronchial hyper-responsiveness and mucus hyper-secretion resulting in bronchoconstriction. According to the ISAAC study, the prevalence of asthma showed a wide range of 1.6-36.8%, with an eight-fold variation seen between the 10 th and 90 th percentiles (3.9-30.6%). [11] Recent reports from India showed a prevalence of asthma in the range of 2.3-16.6%, [12],[13],[14],[15] which is higher than that reported (<1%) earlier. [16] Approximately 50% or more cases of asthma are of an atopic origin.

The key symptoms of asthma are cough, shortness of breath, wheezing and chest tightness. Many cells and cellular elements play a role in asthma pathogenesis; in particular, mast cells, eosinophils, T-lymphocytes, macrophages, neutrophils and epithelial cells. In asthma, the predominant orchestrator of the chronic inflammation is the CD4 or T-helper lymphocyte, producing key regulatory cytokines such as interleukin (IL)-5 and IL-4. [17]

Atopic dermatitis (eczema)

The prevalence of atopic dermatitis in children is estimated to be 10-20%. [18] Studies show that the rate of atopic dermatitis first occurring in infants and persisting into adulthood ranges from 45% to 60%, and the risk of developing respiratory symptoms in later years is around 40-60% (pollen allergy 41.5%; perennial rhinitis 25%; asthma 25%).

Atopic dermatitis (IgE mediated) manifests red, inflamed rashes most often on the arms, legs, ankles or neck. It usually precedes the onset of allergic rhinitis and/or asthma. Acute exacerbations may be weepy and crusted, usually signifying superinfection with Staphylococci. Serum total IgE concentration may be markedly elevated with high levels of IgE against aero-allergens and/or food allergens. Following cutaneous challenge with allergen, there is an initial local response consisting of IL-4 and IL-5 (Th2-type cytokine response), followed by a mixed pattern (interferon [IFN]-γ, IL-4 and IL-5; ThO). [19]

Urticaria

Hives, medically known as urticaria, are caused due to excessive mast cell activity in the skin on exposure with specific allergens. They are red, itchy, raised areas of skin that appear in varying shapes and sizes from a few millimeters to several inches in diameter. Hives can be round, or they can form rings or large patches. Hives are produced by histamine and other compounds released from mast cells. Histamine causes fluid to leak from the local blood vessels, leading to swelling in the skin. [20]

Allergy diagnosis

The diagnosis of allergy is based on a suggestive history, skin tests and/or specific IgE estimation to the relevant allergens and clinical corroboration with allergic symptoms. IgE plays a central role in allergic diseases; thus, in vivo and in vitro tests used in the diagnosis of allergic diseases are directed toward the detection of free or cell-bound IgE. In vivo tests, such as intradermal (ID)/skin prick and provocation tests, and in vitro tests, namely enzyme-linked immunosorbent assay (ELISA)/radioallergosorbent test, are followed for allergy diagnosis. [21],[22]

The common methods of skin testing are prick, ID and prick to prick. Skin prick test (SPT) is the most specific and safe test usually recommended for the diagnosis of immediate type of allergy. [23] The ID test is a more sensitive test, but may yield false-positive results. [24],[25] Another method for skin testing is the prick to prick method, mostly used for juicy fruits and other similar source of allergens. Skin reactions are graded in comparison with the positive control, i.e., histamine diphosphate, or negative control, i.e., phosphate buffer saline.

The histamine release assay is another in vitro test that detects histamine released from the patient's basophils in the presence of specific allergens. [26] The test employs an anti-histamine antibody in a sandwich ELISA to detect histamine released in response to allergen. The histamine released is expressed as a percentage of total histamine release. The cut-off point for significant release is determined in comparison with spontaneous release.

The provocation test (bronchial challenge) is a confirmatory test but is not employed in routine clinical practice because of the risk involved. However, a double-blind placebo-controlled food challenge is recommended to diagnose IgE-mediated allergies to various foods. [23],[27]

Therapeutic strategies

The key elements of allergy management are: (1) preventing the exposure of sensitized individuals to allergen and (2) treating these individuals with therapeutic agents appropriate to the disorder. Precisely, the management of allergic diseases includes allergen avoidance, medication (pharmacological treatment), immunotherapy and patient education. Allergen avoidance is the best treatment, but it may not be possible in case of many outdoor allergens. Pharmacotherapy provides symptomatic relief, and once the drugs are discontinued, the symptoms recur quickly. Immunotherapy is the only treatment modality that acts on effector cells and changes the course of disease.

Allergen-specific immunotherapy (SIT) forms an integrated part of the treatment of type I allergy diseases, [28] reducing the disease severity, improving the quality of life and diminishing the risk and cost of pharmacotherapy. Immunotherapy and pharmacotherapy should be integrated in the treatment for allergic diseases in order to gain the best results. SIT is a gradual immunizing process in which increasing doses of antigens responsible for causing allergic symptoms are administered to a patient to develop tolerance to the offending allergen on natural exposure. It reduces specific cutaneous, nasal, bronchial and/or ocular reactivity to allergen as assessed by in vivo and/or in vitro tests. There is an initial transient increase in serum-specific IgE, followed by gradual decrease over few months of treatment. Then, there is a class switch, where IgG1 shows an increase initially and the IgG4 level increases later as a result of successful immunotherapy. However, these changes may not always correlate with the symptoms.

Good candidates for immunotherapy are patients whose symptoms are not controlled adequately by medications and allergen avoidance measures. Analysis under a World Health Organization position paper revealed that SIT is an effective form of treatment for patients with allergic asthma. [29] Immunotherapy, when properly conducted, has the potential to reduce symptoms and the need for drug significantly. Moreover, it is possible to prevent progression into more severe disease using this therapy. [30] Immunotherapy can be considered effective if a substantial increase (10-100 folds) in allergen-specific IgG4 is induced.

Allergens for immunotherapy

Immunotherapy has been effective with pollen, fungi (molds), animal dander, dust mite, cockroach and hymenoptera sensitivity. [31] The selection of allergens for immunotherapy is based on clinical history, presence of specific IgE antibodies and allergen exposure. Phylogenetically related pollens contain allergens that are cross-reactive. Here, a selection of single pollen within the cross-reactive genus or subfamily may suffice the requirement for immunotherapy. Knowledge of cross-reactivity is important in the selection of allergens for immunotherapy, because limiting the number of allergens is necessary to attain optimal therapeutic dose.

SIT requires extracts with consistent allergenic activity and composition. Standardized extracts are therefore recommended with a defined potency for vaccines and are labeled with a common unit of measure. However, the commercial extracts vary widely in biologic activity and allergen constituents. [32] Natural products are also at risk of being contaminated with allergens from other sources, and the inherent proteolytic enzymes may degrade the proteins. [33] Allergen extracts for both diagnosis and treatment should be stored in a refrigerator between 2°C and 8°C (35.6°-46.4°F), because, at higher temperature, the extracts lose their potency. Concentrated aqueous extracts (1:10 w/v) in 50% glycerin are stable for about 3 years when stored at 4°C (39.2°F), but, without glycerin, they may lose half their original strength within 6 months. [34] A study on the stability of the Periplaneta americana extract shows that epsilon aminocaproic acid (EACA 0.05 M) and sucrose (0.25 M) in combination maintain the shelf-life of the extract for 1 year at 4°C. [35]

Types of immunotherapy

Immunotherapy has been classified according to the route of allergen administration.

Subcutaneous immunotherapy (SCIT): It involves repeated subcutaneous injections of increasing doses of allergen extracts until an optimal maintenance dose is reached [Table 1]. This dose is then injected subcutaneously on a regular basis (at intervals of approximately 20 days) for not less than 3 years. Treating patients with SCIT on the basis of positive allergy tests alone is not justified. Patients receiving immunotherapy need to have proven allergy by skin test or in vitro testing that should correlate with their clinical history.
Table 1: Immunotherapy protocol

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Studies evaluating the long-term efficacy of subcutaneous immunotherapy with inhalant allergens have been undertaken in patients with rhinitis and asthma. In one report, the long-term advantages of this therapy have been shown over pharmacotherapy. [36] The relapse of symptoms after discontinuation of pharmacotherapy was faster (1 month) than immunotherapy (1 year). A pollen immunotherapy study of 3 years has demonstrated the favorable effects in clinical parameters as well as increased production of specific IgG4, TGF-β and IL-10 and decreased IgE binding affinities. [37] Another 10-year follow-up study investigating the time course changes in specific IgE and IgG4 in serum found that the IgE titer begins to decrease with many years of treatment, and increase in IgG4 plays a significant contribution in the clinical efficacy of immunotherapy. [38]

There are reports suggesting that allergen-SIT also prevent onset of new sensitization in allergic patients. [39] Administration of allergens in patients by the subcutaneous route might cause local and/or systemic reactions, such as urticaria, asthmatic attack and/or life-threatening anaphylactic shock. Therefore, attempts have been made to reduce therapy-induced side-effects. These include the adsorption of allergen extracts to adjuvant to delay the systemic release of allergenic material from the site of administration and the chemical modification of allergens to reduce their allergenicity and mutations to abrogate allergenic activity but retain immunogenicity.

Sublingual immunotherapy (SLIT): SIT by the subcutaneous route is effective for the treatment of allergic asthma and rhinitis, but it may be associated with severe or even fatal systemic reactions. [40],[41] Therefore, an alternative route of allergen administration has been proposed involving mucosal absorption. SLIT is safe because the oral mucosa lacks proinflammatory cells and is rich in Langerhans-like dendritic cells. [42],[43] Sublingual immunotherapy is raising a lot of interest as a non-invasive procedure and is demonstrated to be efficacious. But, it requires high doses of allergen, i.e., 50-100 fold more than that administered through the subcutaneous route. [44],[45],[46]

SLIT is reported to be effective as subcutaneous immunotherapy in reducing allergic symptoms and medication requirement. [47],[48],[49],[50] Here, the patients are instructed to hold the extract (drops) under the tongue for 2 min and then swallow the same. The dose is increased once every 3-4 weeks or earlier until a maintenance dose is reached, with minimal or no side-effects. Contact of the allergen with the oral mucosa is crucial for the success of SLIT. SLIT showed comparable efficacy with SCIT in allergic rhinitis patients, with less than 5% side-effects, and was safer even in children of less than 5 years of age. [50]

Oral immunotherapy: The extracts are given through the mouth in the form of enteric-coated capsules. Here, the allergen tolerance was reported to improve due to deviation of TH2/TH1 and regulation of IgE production. [51] Studies show a clear clinical effectiveness supported by significant symptom improvement and decrease in dosage of drugs required to control the symptoms. [52],[53] However, with high doses, adverse reactions like intestinal bleeding were observed in this form of immunotherapy. [54],[55]

Intranasal immunotherapy: Of 18 studies available, 17 reported significant improvement in rhinitis by reduction of nasal sensitivity and local immunological responses. [56],[57] Both aqueous extracts and dry powders have been tried in nasal immunotherapy. Apparently, nasal therapy exerts its action only on the target organ and the efficacy of the treatment requires pre-seasonal administration. Here, mild adverse reactions such as rhinitis and itching in the nose have been reported.

Mechanism of Immunotherapy

Studies have shown modest reduction in allergen-specific IgE levels and induction of allergen-specific IgG subclasses after immunotherapy. [29],[58],[59],[60] Durham et al. suggested that the IgE allergen binds to CD23 on the surfaces of B cells leading to stimulation of allergen-specific T-cell clones. But, in patients getting immunotherapy, IgG antibodies could inhibit IgE-facilitated allergen binding by B cells and presentation to T cells. [61] Another surface receptor, CD32, is part of a large population of B cell co-receptors that act to modulate signaling. It has a low affinity for IgG antibodies and down-regulates IgE antibody production in the presence of IgG. CD32 (Fc II) receptor is involved in the regulation of the B cell response to antigen. [62] However, the importance of blocking antibodies (IgG) was questioned because induction of IgG is not always associated with clinical improvement after immunotherapy. [63] Recent studies carried out in defined molecular and cellular systems have rekindled interest in the concept of blocking antibodies. [64] Gradually, it was proven that immunotherapy altered the cytokine profile from a TH2 cytokine-dominated response (IL-4 and IL-5) to a TH1-type response with a local accumulation of cells producing IFN-γ. [65] Immunotherapy acts on effector cells inhibiting the release of inflammatory mediators. Early effects of immunotherapy are related to mast cell and basophil desensitization. Intermediate effects are associated with changes in allergen-specific T cells and late effects are on B cells and IgE as well as mast cells, basophils and eosinophils. [66]

Control of IgE synthesis is attributed to the actions of mutually antagonistic subsets of CD4+ T cells. Later, it was acknowledged that activated T cells and their products play a major role in the pathogenesis of allergic diseases, and allergen-specific T cells were considered as the major target for SIT. SIT is associated with a decrease in IL-4 and IL-5 production by CD4+ TH2 cells and a shift toward increased IFN-γ production by TH1 cells. Recent reports indicate that immunotherapy acts by modifying CD4+ T cell responses either by immune deviation, T cell anergy and/or both. [67] Studies in mice and in human subjects have suggested the presence of various types of T cells with regulatory activity (ie, T cells with inhibitory effects on immune responses), including TR cells (producing IL-10 and possibly TGF-β), CD4+ CD25+ T cells (possibly TGF-β) and TH3 cells (also TGF-β). [68] Induction of IL-10 might block B7/CD28 co-stimulation. [69] IL-10 has a number of documented anti-allergic properties that might be important to immunotherapy. [70]

Sublingual immunotherapy operates through a different route, wherein the allergen is captured by Langerhans-like dendritic cells in the oral mucosa and, subsequently, the dendritic cells mature and migrate to the proximal draining lymph nodes. The role of these lymph nodes lies in their preferential production of blocking IgG antibodies and the induction of T lymphocytes with suppressive function. One explanation for the success of SLIT is the profound difference between oral Langerhans cells and their skin counterparts. Oral Langerhans cells exhibit constitutive high expression of the Fc portion of IgE (FcεRI), major histocompatibility complex (MHC) class I and II, as well as co-stimulatory molecules (CD40, CD80/B7.1, CD86/B7.2), which suggest the specific function of these cells within the regional immune system of the oral mucosa. [71] A recent study [72] revealed that the lipopolysaccharide receptor CD14, present on both nasal and oral myeloid dendritic cells, was at higher density on oral dendritic cells. Allergen delivery through the sublingual-swallow route appears to be more efficient than either route alone, which suggests an inevitable absorption of allergen through the gastrointestinal tract that potentiates the induction of oral mucosal tolerance. [73]


  Immunotherapy Trials in Asthma and Rhinitis Top


Trials supporting immunotherapy

Clinical efficacy of immunotherapy in rhinitis and asthma using potent standardized extracts in carefully selected patients has been well documented by many double-blind placebo-controlled studies. However, only a few studies have demonstrated a low degree of clinical efficacy. [74] A metaanalysis of clinical trials of allergen immunotherapy has shown benefits for the treatment of allergic conditions/asthma; however, the major risk associated is systemic reactions (anaphylaxis). Immunotherapy is effective and well tolerated in children. Besides, it prevents the development of asthma in children having allergic rhinitis. Immunotherapy with hymenoptera venom allergens has been reported to give almost 100% benefits in patients. Several clinical trials have been performed the world over demonstrating beneficial effects of this therapy using clinico-immunologic parameters. [75],[76] The fundamental question regarding immunotherapy is whether it has the potential to provide long-term benefit after its discontinuation. Studies suggest that immunotherapy has a prolonged beneficial effect, lasting several years after the discontinuation of treatment. [77] To the best of our knowledge, more than 75 trials in asthma and more than 18 trials in allergic rhinitis has been reported in the literature. [78]

Immunotherapy trials with mixed grass-pollen allergoid used in a low-dose schedule (maximal dose: 2000 PNU) in 19 patients and in a high-dose schedule (maximal dose: 10,000 PNU) in 20 patients, with 18 patients in the placebo group, were conducted. Both the antigen immunotherapy groups presented a significant reduction in nasal and skin sensitivity and a significant increase in IgG. [79],[80] A highly significant correlation was recorded between nasal symptom and medication scores and the results of nasal challenges. [81] A double-blind, multicenter immunotherapy trial in children using a purified protein of Cladosporium herbarum showed a decrease in bronchial hyper-reactivity (BHR) and specific IgE and increase in specific IgG, with a marked increase in the ratio of specific IgG/specific IgE. [82],[83] A double-blind placebo-controlled rush immunotherapy with the Alternaria extract showed decreased symptom and medication scores, skin tests wheal and increased specific IgG significantly. [84] Immunotherapy trials with Dermatophagoides pteronyssinus and D. farinae showed improvement in asthma patients allergic to mite. [85],[86] A double-blind placebo-controlled immunotherapy trial of house dust mite demonstrated reduced bronchial sensitivity to allergen. [87] An immunotherapy trial with D. pteronyssinus showed improvement in asthma patients allergic to mite with increase in IgG. [88] A double-blind, multicenter immunotherapy trial in children using purified D. pteronyssinus resulted in a significant increase of specific IgG antibodies. [89] Successful immunotherapy with D. pteronyssinus in perennial childhood asthma was associated with a slight mean rise of serum IgG antibody to the mite antigen in contrast to the placebo group. [90] A double-blind, rush immunotherapy with standardized D. pteronyssinus showed improvement in bronchial provocation tests. [91] Further, a double-blind placebo-controlled trial with D. pteronyssinus demonstrated reduction in symptomatic medication than in the control group. [92] SIT with standardized D. pteronyssinus showed improvement in symptoms and increase in specific IgG. [93] A double-blind trial of immunotherapy in cat allergen-induced asthma showed a reduction in skin reactivity to the cat extract as well as a significant mean reduction in bronchial sensitivity to the same extract, with significant increases in specific IgG. [94],[95] Immunotherapy with the cat extract was well tolerated, significantly decreasing the skin and bronchial responses to the cat extract and specific IgE and significantly increasing the specific IgG antibodies. [96],[97] A double-blind trial of immunotherapy with cat allergen showed reduction in bronchial sensitivity toward cat, decrease in BHR and symptoms as well as increase in IgG. [98],[99] A double-blind immunotherapy trial with dog dander extract also showed decrease in conjunctival sensitivity and skin test wheal response and increase in IgG. [100],[101]

Trials not supporting immunotherapy

However, few studies on allergen immunotherapy did not find beneficial results. In one trial of ragweed allergic asthma patients (N = 25), there was no significant response in asthma or hay fever symptoms. [102] In another double-blind placebo-controlled trial with D. pteronyssinus, no improvement was observed in patients with asthma sensitive to house dust mite. [103]

The antigenic components, mainly proteins, are many in most of the antigens, except in venom. The response hence was very good with venom immunotherapy. The multiple proteins and the unwanted substances (fats and carbohydrate) in crude antigen (used at present) reduce the efficacy of immunotherapy. Efforts are being made to isolate the specific antigenic moiety in every antigen, but the cost and the procedure of procurement is tedious and is not at present commercially viable. The potency of the antigen mostly differs in every batch and is a cause of concern for the efficacy. However, there are natural variations in the characteristics of the antigen from place to place due to a difference in the soil characteristics and the environment. Development of new sensitivities has been noticed in few cases undergoing immunotherapy, for which no definite explanation is available. Standardization of antigen is highly essential for uniformity of potency and increasing the efficacy, but is a difficult task. The most important cause of reduced efficacy of immunotherapy in certain cases is due to its overuse and misuse.

Allergen immunotherapy in India

Immunotherapy is practiced in India since the last three decades. In an open study at the V.P. Chest Institute, Delhi, 50% of the seasonal allergic rhinitis cases showed considerable reduction in their symptom score and drug intake after 2 years of immunotherapy with mixed allergen vaccines. [104] Further, a placebo-controlled immunotherapy trial with a single allergen preparation of Cocos nucifera pollen showed significant clinical improvement and immunological changes as compared with the placebo group. [105] An open comparative trial taking immunotherapy versus inhaled budenoside showed faster improvement in symptoms of asthma with drug therapy. But, the decline in benefit after cessation of treatment was more rapid in patients on corticosteroids than in patients on immunotherapy. [36] Immunotherapy in patients suffering from house dust allergy showed decrease in IgE symptoms and increase in specific IgG. [106] Allergen-SIT with mixed allergen extracts (vaccine) in nasobronchial allergy showed significant improvement in symptoms, lung function and reduced skin sensitivity in patients of asthma and rhinitis. [107] A single-blinded immunotherapy trial for 3 years with Sorghum vulgare (Jawar) pollen extract in 51 patients of asthma resulted in significant symptom improvement in 47% of the patients in the immunotherapy group as compared with 20% in the pharmacotherapy group. [108] A double-blind placebo-controlled immunotherapy trial with mosquitoes for 1 year in 40 patients of asthma and rhinitis showed significant symptom improvement, PC20, significantly high levels of IgG4 and reduced skin reactivity, IgE levels and decreased IgE/IgG4 ratio. [109] A double-blind control study of 1 year immunotherapy in 85 cases of asthma and rhinitis, including healthy controls, observed significant improvement in symptom score, skin sensitivity, airway reactivity (PC20), IgE/IgG4 and IgG1/IgG4 ratio. There was no significant difference in improvement by using single antigen or multiple antigen (up to 5) for immunotherapy. There was also a positive correlation with increase in IgG4 levels and clinical improvement in the study. This emphasizes that use of multiple antigens for immunotherapy is also justified. [110]


  Future Immunotherapy Strategies Top


Reports from China on future therapeutic strategies suggest the beneficial effects of BCG immunization, [111] resulting in TH1 response and prevention of sensitization. Studies indicate an increased risk for sensitization on exposure to environmental allergens during infancy. [112] Thus, immunization with an antigen early in life (TH1 response) could prevent a subsequent TH2 response to the same antigen. Also, creating a pervasive TH1-dominated environment could influence the response occurring to the exposure of other allergenic proteins. Using various allergen-specific methods with adjuvants or DNA-based immunization at an early age to high-risk children is expected to give a long lasting protective TH1 response. [113] Here, the problem is to reliably identify children at high risk. With the developments in the human genome project, it has become possible to identify genes responsible for allergy/asthma that serve as markers for identifying children at high risk. These children can be benefited by proper immunotherapy at an early age before their immune responses get locked up in TH2 immunity.

Studies suggest that recombinant allergens show comparable IgE binding to their natural counterparts. [114],[115] Several studies with recombinant allergens have been performed to improve the efficacy and safety of immunotherapy. [116] Modified derivatives of major birch pollen allergen, Bet v1, have been tried successfully in two studies on immunotherapy. [117],[118] Recombinant allergens also offer the possibility of developing hypo-allergens with reduced IgE reactivity but intact immunogenicity.

Peptides are small fragments of protein that are too small to be recognized by IgE for cross-linking on mast cells. Synthetic peptides representing T cell epitopes, if presented without co-stimulation, can induce anergy to subsequent challenges with the peptide or full length protein. [119],[120],[121] Peptide allergen immunotherapy has been studied best with cat major allergen Fel d 1 [122] and with hymenoptera venom major allergen phospholipase A2. [123] Most recently, investigators have examined a collection of overlapping peptides of Fel d 1, each with 12 amino acids in length, which covers the whole protein. [124],[125] Because of the peptide overlap, they affect many T cells in a wide variety of different individuals.

The biology of CpG motifs had been reviewed by Krieg and Wagner, [126] followed by a review of toll-like receptor by Zuany-Amorin et al. [127] The potential use of CpG in the treatment of allergic rhinitis [128] and asthma has been suggested. [126],[127] Synthetic CpG motifs are either mixed with an allergen vaccine or covalently conjugated to an allergen. In the first trial of this concept, a conjugated product was developed by Dynavax Technologies Corporation that has an average ratio of six CpG residues per ragweed Amb a 1 molecule. Studies reveal that such conjugates promote allergen-specific IgG2a antibody production, a marker for TH1 responses in mice. [129] Studies in murine models have demonstrated that DNA immunization strategies prevent the development of antigen-specific IgE synthesis, airway hyper-responsiveness or food-induced anaphylaxis and induce inhibitory CD8 cells. [121],[122],[123]

The difference in environment, climate, soil characteristics and presence of different allergens present in India has prompted us to prepare a "Guidelines for practice of Allergy in India" to include most of the global recommendations, with few recommendations being modified to suit the Indian situations. The first such guidelines were prepared and published in 2009. [130] An editorial comment mentioning the scientific facts as known today further emphasizes the efficacy of allergen immunotherapy. [131] However, it is further emphasized that allergen immunotherapy should be prescribed under the direct supervision of a trained allergist/immunologist in the office having facilities with appropriate equipment, medications and personnel to deal with anaphylaxis. [130]

 
  References Top

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Abstract
Introduction
Allergic Diseases
Immunotherapy Tr...
Future Immunothe...
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