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The ACVD task force on canine atopic dermatitis (XXIV): allergen-specific immunotherapy.

Allergen-specific immunotherapy (ASIT) has been used for years to treat dogs with atopic dermatitis (AD) and humans with atopic diseases. The efficacy of ASIT has been well documented for humans with respiratory atopic diseases and stinging insect allergy, but its effectiveness seems more controversial for patients with AD. In spite of insufficient evidence derived from randomized controlled trials, multiple open studies and a large body of clinical observations suggest that ASIT is effective in controlling the clinical signs of dogs with AD. As a result of the scarcity of evidence from controlled trials, the true efficacy of ASIT, and the optimal protocols for allergen dose and frequency of injection are currently unknown. Allergen-specific immunotherapy nevertheless may be included in the treatment of canine AD because of its potential advantages and limited disadvantages compared to other forms of therapy. There is no evidence, however, for the preference of any specific treatment protocol. The predictive value of historical, clinical and immunologic features related to the efficacy of ASIT in dogs with AD are discussed in this paper. Adverse reactions, and the requirements for monitoring of patients receiving ASIT, then are reviewed and detailed. Finally, this review highlights aspects of ASIT where further research and controlled studies are needed.

Allergens↗

Recombinant allergens for diagnosis and therapy of allergic diseases.

A considerable number of cDNAs coding for allergens have been isolated and expressed. Structural and immunological similarities between recombinant allergens and natural allergens indicate that a sufficient panel of recombinant allergens can be produced for diagnosis and therapy of allergic diseases. Recent studies document the successful in vitro and in vivo determination of a patient's allergen profile (allergogram) with recombinant allergens and encourage the use of recombinant allergens for specific therapy.

Allergens↗

New insights into the mechanisms of allergen-specific immunotherapy.

PURPOSE OF REVIEW: Specific immunotherapy represents the only curative treatment of a specific allergy, and is therefore of great interest in terms of immunological mechanisms and therapeutic developments. RECENT FINDINGS: Allergen-specific regulatory T cells are induced after the initiation of specific immunotherapy, and are assumed to suppress effector T cells directly mediating allergic inflammation. Therefore regulatory T cells may play a key role in the re-induction of allergen tolerance. Multiple pathways in many systems are described to promote or enhance regulatory T cells. This review summarizes the current view on immunological mechanisms leading to and coming from regulatory T cells. SUMMARY: The highlighted mechanisms may not only contribute to improved specific immunotherapy, but also give insight into a clinically relevant therapy targeting regulatory T cells. The approach of addressing endogenous regulatory mechanisms specifically controlling inflammation instead of targeting inflammation itself is relevant for future pharmacological developments.

Allergens↗

Acute polyradiculoneuropathy occurring after hymenoptera stings: a clinical case study.

Hymenoptera stings may be responsible for both local and systemic reactions; these can be immediate or delayed, depending on the time between the sting and the development of signs or symptoms. Delayed clinical reactions have been reported, although unusual, due to serum sickness and/or affecting organs or systems generally not involved in the immediate reaction, such as heart, kidneys, central and peripheral nervous systems. This paper describes the clinical and immunological findings in a 51-year-old subject, who, after two stings of paper wasps, the second one after the third venom immunotherapy (VIT) injection, presented immediate large local and systemic allergic reactions which quickly improved after e.v. methylprednisolone administration. About 40 hours later, he developed acute polyradiculoneuropathy with muscle weakness, paresthesia, difficulties in standing up and walking. Skin tests and specific IgE determination showed allergy to paper wasp. The activation, by wasp venom, of peripheral blood mononuclear cells in primary culture, evaluated by tritiated thymidine incorporation proliferation assay, showed an important hypersensitivity to wasp venom. Therefore our results suggest the hypothesis that the polyradiculoneuritis causative etiopathogenetic mechanism might be a delayed immunological response to wasp antigens followed by an allergy-triggered autoimmune reaction, as previously suggested by other authors; they found lymphocytic infiltrates in demyelinization areas and at perivascular levels, by histologic examination of autoptical and bioptical material of patients with nervous system lesions after hymenoptera stings.

Acute Disease↗

Immunologic aspects of asthma.

Asthma often, but not always, is the result of an IgE-mediated allergic reaction to an airborne antigen. The chain of biochemical reactions is now fairly well defined. These reactions generate an immediate smooth muscle bronchoconstriction and a late inflammation 4 to 24 hours later. This article describes the most important allergens in the community, home and workplace, and discusses procedures for diagnosis and management.

Allergens↗

[Immunological aspects of bronchial asthma].

Advances in understanding of bronchial asthma are to be expected from more detailed information on the immuno-pathological mechanisms involved. Reaginic IgE antibodies are responsible for the great majority of extrinsic asthma, but in some cases immune complexes could probably be also important. A great progress has been achieved after reproducible methods for detecting cellular and serum specific IgE antibodies were introduced. Moreover, the immunological and biological changes induced by immunotherapy are better known. Standardization and purification of allergenic extracts is now under study in many laboratories, our own included. As concerns the intrinsic asthma attempts to demonstrate the importance of (auto) immune mechanisms have been performed. The results of these studies are reported.

Antibody Formation↗

Survey of patients after discontinuing venom immunotherapy.

BACKGROUND: Venom immunotherapy rapidly reduces the risk of a systemic sting reaction in adults from 30% to 70% to less than 2%. When venom immunotherapy is stopped after 5 years or longer, the risk of a systemic sting reaction is 5% to 15% during the first few years after stopping treatment. It is uncertain whether systemic sting reactions will occur more than 5 years after discontinuing venom immunotherapy and whether treatment can be safely stopped in some patients after less than 5 years. OBJECTIVE: The purpose of this study is to estimate the risk of systemic reaction to a sting 10 years after discontinuing treatment and the relative risk after 3 years of treatment compared with that after 5 years or more of treatment. METHODS: Among all patients who had venom immunotherapy at our center, we identified 395 patients who stopped treatment: some had dropped out of therapy early (6-24 months), some stopped after 3 to 4 years, and most completed 5 years or more of venom immunotherapy and were advised to stop by the allergist (many as part of our reported studies of discontinuing venom immunotherapy). RESULTS: Contact was made with 194 patients, including telephone interviews for sting history and requests to visit the office for skin testing and blood sampling. Of these patients, 74 had been included in our original study of patients who had 5 years or more of venom immunotherapy and had sting challenges after 1 to 5 years off venom immunotherapy, as previously reported. Of the 74 in that original study, 61 were reached for this survey, and 30 reported recent stings, with 5 systemic sting reactions. Another 133 patients who had stopped venom immunotherapy were reached: 82 had 5 or more years of venom immunotherapy, 20 had 3 to 4 years of venom immunotherapy, and 31 had less than 2 years of venom immunotherapy. Of 51 patients stung from this group, 27 had 5 or more years of venom immunotherapy (no systemic sting reactions), and 24 had less than 5 years of venom immunotherapy (3 systemic sting reactions). We have now observed a total of 113 patients who had 5 or more years of venom immunotherapy and were stung after stopping. Sixteen (14%) had systemic sting reactions; most were mild, but 4 were severe. Systemic sting reactions occurred in 12 (10.7%) of 112 patients stung in the first 4 years off venom immunotherapy and 5 (10%) of 50 stung more than 5 years off venom immunotherapy. In 4 of 8 patients with current systemic sting reactions, the skin test response was negative, although the venom-IgE response was positive at the previous encounter. All systemic sting reactions were similar in pattern and severity to prevenom immunotherapy reactions in the same patient. CONCLUSIONS: We conclude that the risk of systemic sting reactions when venom immunotherapy is stopped after 5 years or longer remains in the reported range of 5% to 15% in the 5 to 10 years after stopping venom immunotherapy. This risk of systemic sting reactions does not seem to decrease over time, unlike the progressive decline in immunologic markers (skin test and venom-IgE responses). To prospectively assess the risk of recurrent systemic sting reactions, there is a need for sting challenge studies of patients who have been off venom immunotherapy for 5 to 10 years and patients who have stopped venom immunotherapy after just 3 to 4 years treatment.

Adult↗

Absence of systemic immunologic changes during dose build-up phase and early maintenance period in effective specific sublingual immunotherapy in children.

BACKGROUND: Sublingual immunotherapy (SLIT) has been reported to be a safe treatment for inhalant allergies in children. Yet the immunologic mechanisms resulting in clinical improvement are poorly understood. OBJECTIVE: To identify early systemic immunologic changes during the first 8 weeks of clinically effective SLIT to grass pollen, tree pollen or house dust mite in paediatric patients with allergic rhinoconjunctivitis and/or asthma. METHODS: Peripheral blood mononuclear cells and plasma samples of 13 children with reduced symptoms after 1 year of SLIT were obtained before therapy and at 2 and 8 weeks after the initiation of SLIT. Allergen-specific lymphocyte proliferation assays were performed, and allergen-induced cytokine production (IL-2, IL-4, IL-10, IFN-gamma, and TGF-beta(1)) was measured by ELISA and flow cytometry. Allergen-specific IgE, IgG1, IgG4, and IgA levels in plasma samples were determined in ELISA. RESULTS: During the first 8 weeks of successful SLIT, allergen-specific lymphoproliferation (n=13) as well as levels of allergen-specific intracellular (n=8) and secreted cytokines (n=9) did not change significantly. In addition, no alterations in levels of allergen-specific Igs (n=7) were observed. CONCLUSION: We could not find any early systemic immunologic changes during the first 8 weeks of clinically effective SLIT to inhalant allergens in paediatric patients with allergic rhinoconjunctivitis and/or asthma.

Administration, Sublingual↗

Cry j 1-induced synthesis of interleukin-5 and interferon-gamma by peripheral blood mononuclear cells of patients with seasonal allergic rhinitis due to Japanese cedar pollens.

This study comprised 130 adult patients with Japanese cedar pollen-specific IgE in the serum and 15 non-atopic individuals. Eighteen patients had no seasonal aggravation of nasal symptoms during the pollen season in 1998 (asymptomatic group). Forty-two patients had not been treated previously with immunotherapy and were treated with antihistamine tablets during the pollen season in 1998 (medication group). Sixty-one patients had undergone variable periods of immunotherapy using pollen extracts, and they were further divided into a good-IT group who responded markedly to immunotherapy and a poor-IT group who responded poorly to immunotherapy. The remaining nine patients had been treated with immunotherapy for more than 12 years and all of them had stopped immunotherapy by the end of May 1997 because they had no nasal symptoms for the last three pollen seasons and were considered to be cured of seasonal allergic rhinitis (cure group). Peripheral blood mononuclear cells (PBMCs) were collected from each subject during the cedar pollen season in 1998 and were stimulated for 96 h with 10 micrograms/ml Cry j 1. The concentrations of interleukin-5 (IL-5) and interferon-gamma (IFN-gamma) in the culture supernatant were determined using an enzyme-linked immunosorbent assay. The levels of IFN-gamma did not differ significantly among the non-atopic group, the asymptomatic group, the medication group, the poor-IT group and the good-IT group. The level of IL-5 in the asymptomatic group was not different from that in the non-atopic group. The levels of IL-5 in the medication group, the good-IT group and the poor-IT group were significantly higher than in the non-atopic group. The level of IL-5 in the good-IT group, but not in the poor-IT group, was significantly lower than in the medication group. The level of IL-5 in the cure group was not significantly different from in the non-atopic group, and the level of IFN-gamma in the cure group was significantly lower than in the non-atopic group. In conclusion, immunotherapy can decrease the pollen allergen-induced synthesis of IL-5, but not of IFN-gamma, and this immunological modulation is involved in the working mechanism of immunotherapy related to its clinical efficacy. A tolerance or anergy of both TH1 and TH2 cells under allergen stimulation may be an immunological indication of cure after the treatment of seasonal allergic rhinitis. Thus, the suppression of synthesis of IL-5 and IFN-gamma by allergen-stimulated PBMCs is likely to be a reliable criterion for a possible cure of seasonal allergic rhinitis after immunotherapy.

Adult↗

[Anaphylaxis caused by a mosquito: 2 case reports].

Allergy to mosquitoes that produces anaphylaxis is very exceptional. We present two observations of anaphylaxis to mosquitoes with good correlation between the clinical history and the immunological indications of which the basophil activation test proved to be effective. The many allergens of mosquitoes are contained in the juices and salivary glands and their molecular weights are between 22 and 95 kD. Specific immunotherapy, which uses whole body extracts of mosquito, gives good results of protection that induces excellent tolerance and has very good efficacy.

Adult↗

Immunological defects in allergic asthmatic children and working mechanisms of hyposensitization--a review.

Patients with allergic diseases are characterized by the presence of elevated serum IgE and specific IgE antibodies against a variety of environmental allergens, especially house dust, mites and molds in Taiwan. A series of studies on allergic asthmatic children have been conducted to explore the non-immunological and immunological causes for their augmented production of IgE antibody and to explore the working mechanisms of hyposensitization. The results showed that the patients had multiple defects in their defects in their defense mechanisms, including hyper-permeability of mucosae, hyperreactivity of target organs, defective phagocyte functions, and deficient helper and suppressor T-cell functions. Hyposensitization was able to partially correct the immunological aberrations. More over, a newly found lymphokine termed "T-cell growth factor" or "interleukin 2" may be used not only as an indicator for the initiation and termination of hyposensitization, but may also provide a promising tool for the treatment of allergic diseases in the future because of its capability of enhancing and expanding allergen-specific suppressor T cells.

Allergens↗

Immune and biochemical mechanisms in the allergic disease of the upper respiratory tract; role of antibodies, target cells, mediators and eosinophils.

The pathways leading to the development of the allergic state and subsequently to the characteristic inflammatory response are complex in nature and result from an interplay between immunologic and biochemical events. Along these pathways a number of intrinsic factors, i.e., handling of antigens at mucosal level, transient immunodeficiency states, especially in the secretory IgA system, impairment in the IgE regulatory mechanism, modulation of cyclic nucleotides leading to mediator release and a "feedback" inhibition control provided by histamine and eosinophil derived products greatly dictate the outcome of events associated with allergic inflammation.

Allergens↗

IgE-mediated allergen presentation and blocking antibodies: regulation of T-cell activation in allergy.

It is well established that both the production of IgE by B lymphocytes and the maturation and recruitment of eosinophils in late-phase reactions are dependent on the activation of allergen-specific type-2 T-helper cells. What is less well known is the fact that efficient activation of allergen-specific T cells upon low-dose exposure to allergens is critically dependent on IgE-mediated or -facilitated allergen presentation. In fact, changes in the level of IgE-mediated allergen presentation may account for many of the immunological effects described for specific immunotherapy or anti-IgE treatment. This review aims to summarize the current knowledge, and will discuss the clinical relevance of blocking IgG antibodies induced by specific immunotherapy and anti-IgE monoclonal antibodies that both interfere with IgE-mediated allergen presentation.

Allergens↗

Sublingual immunotherapy of allergic diseases.

The only disease-modifying treatment that is available for allergic patients is allergen-specific immunotherapy. Two competing application forms are used: subcutaneous immunotherapy, which has been used for > 90 years, and a relatively new immunotherapy where the allergen is applied sublingually. Numerous studies have shown efficacy for subcutaneous immunotherapy and have identified possible mechanisms that are responsible for the observed reduction in allergic responses. In contrast, the efficacy of sublingual immunotherapy has not been documented to the same degree and the responsible immunological mechanisms have not yet been clearly defined. This review focuses on the published clinical and experimental data on sublingual immunotherapy and points at possible mechanisms of how sublingual immunotherapy may differ from subcutaneous immunotherapy in its mode of action, and also discusses the potential advantages and pit falls of both therapies.

Administration, Cutaneous↗

[Atopy and RAST. Diagnostic, therapeutic and standardization problems. Experimental contribution (allergy to antibiotics)].

The authors outline the immunological and immunogenetic bases of atopy, as well as the radioimmunological techniques employed in the allergological diagnosis and purification as well as standardization of the allergens. The latest trends of the allergological immunotherapy are examined, covering fundamentally two wide fields: the possibility to elicit an aspecific immunological tolerance (soluble suppressor substances of IgE response; Asp-Ser-Asp-Pro-arg pentapeptide, D-GL copolimer conjugated aptens) or the specific induction of "suppressor" mechanisms (allergoids, modified allergens). The preliminary results obtained on sera of patients with a symptomatology highly indicative of penicillin allergy, employing RAST Penicilloil G and Penicilloil V, are also reported.

Allergens↗

Evaluation of the adverse effects of long-term hyposensitization.

This study was undertaken to determine if long-term hyposensitization causes late sequelae, particularly those reflecting aberrant immunologic responses. Atopic individuals receiving five or more years of hyposensitization with allergenic extracts showed no increased autoimmune, collagen vascular, or lymphoproliferative disease. In addition, chronic hyposensitization did not have adverse effects on immunologic reactivity as assessed by a number of immune parameters. Particularly noteworthy was the absence of immune complexes in the serum of patients undergoing long-term hyposensitization. This study represents the first systematic investigation of potential adverse effects of long-term hyposensitization.

Adolescent↗

Recent advances in bronchial asthma.

Bronchial asthma in childhood is a major pediatric problem for the physician, both as an acute emergency and as a chronic disease. To adequately manage asthma, one must have a firm understanding of its pathogenesis, and the clinical aspects of diagnosis and therapy. We review important developments in the area of the basic mechanisms causing bronchial obstruction, and methods of measuring the abnormalities present. This presentation includes the fields of neuropharmacology, biochemistry, immunology, and pulmonary physiology. With this background, the clinical aspects of diagnosis and therapy are explored. The role of the allergy history, skin testing, measurement of serum IgE antibodies, and target organ provocation testing are placed in perspective. Therapy involving avoidance measures, use of pharmacologic agents and injection therapy with inhalant allergens are discussed in detail.

Asthma↗

[Immunotherapy in allergic diseases. Evaluation of short-term efficacy of aluminum hydroxide-absorbed slow-release preparations].

Clinical and immunological changes after immunotherapy (ITS) for respiratory allergy were evaluated in 29 subjects during a one year follow up period. No adverse effects were noted with alum-absorbed allergen extracts. However, only patients receiving ITS for grass pollens demonstrated clinical improvement and blocking IgG increase as compared with those with multiple allergen sensitivity.

Adolescent↗