Prospects for CpG based immunotherapy in asthma and allergy

Although administration of protein allergens to subjects with allergic rhinitis and asthma is effective in modulating the immune response and reducing symptoms, alternative strategies to minimize the allergenicity of protein immunotherapy while improving the effectiveness are currently being investigated in animal models of asthma and in human subjects with allergic rhinitis. CpG DNA, and CpG DNA conjugated to a protein allergen have shown promise in animal models of asthma and have entered phase I/II clinical trials. Further, clinical trials are needed to determine whether any of these CpG DNA based therapies are safe and effective to use in subjects with allergic rhinitis and asthma.     

Circulating immune complexes during immunotherapy in allergy to dog

Circulating immune complexes (CIC) were determined from dog-allergic asthmatic children (n = 35) receiving immunotherapy with dog dander and hair extract. The results from CIC are expressed in SDU (standard deviation units) and presented as follows: pretreatment results (n = 20), rush results (n = 11), mid-schedule results (n = 20), maintenance results (n = 15) and the results of the placebo-treated group (n = 12). The results of the placebo-treated group (n = 12) and those of the untreated atopic (n = 12) and non-atopic (n = 14) were controls. CIC levels were analysed by means of KgB-ELISA (conglutinin binding enzyme linked immunosorbent assay), C1qB-ELISA (C1q-binding enzyme linked immunososrbent assay), RFb-ELISA (rheumatoid factor binding enzyme linked immunosorbent assay) and by PIPA (platelet 125J-labelled staphylococcal protein-A test). The CIC level determined by KgB-ELISA in dog-allergic asthmatic children was higher than that of the atopic controls (P less than 0.05) already before the onset of the hyposensitization. During conventional hyposensitization with dog dander and hair the CIC level remained the same as before treatment. On day 5 of rush hyposensitization the mean level of CIC showed no increase when compared with the pretreatment values. A statistically significant correlation (P less than 0.01) was observed between the dog dander and hair-specific IgG antibodies and the CIC level measured by KgB-ELISA during the maintenance period of conventional immunotherapy. The samples of sera to measure this correlation were collected before the injection of allergen and after 2 weeks of injection during maintenance treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Towards immunotherapy for peanut allergy

PURPOSE OF REVIEW: Food allergy is a major cause of life-threatening hypersensitivity reactions. Peanut allergy is the most serious of the hypersensitivity reactions to foods due to its persistence and high risk of severe anaphylaxis. Currently, strict avoidance of the allergenic food and ready access to self-injectable epinephrine is the 'standard of care' for food allergy. Based on extensive characterization of food allergens and a better understanding of the immunological mechanisms underlying allergic disease, promising therapeutic modalities for food allergy treatment and prevention are being developed. RECENT FINDINGS: Immunotherapeutic strategies include peptide immunotherapy, mutated protein immunotherapy and DNA immunization, which all strive to decrease the deleterious Th2 response. Another approach already in clinical trials for peanut allergy is the anti-IgE therapy which prevents circulating IgE from binding to effector cells, consequently decreasing clinical symptoms after peanut ingestion. In order to be applicable, these strategies must be well tolerated, inexpensive and easily administered. Realistic treatment options would likely involve a combination of different approaches. SUMMARY: Food allergy affects approximately 4-6% of children and 3-4% of adults. Peanut allergy can be devastating as reactions range from urticaria to severe anaphylactic shock and death. The only preventive measure for peanut allergy is strict avoidance of the incriminating food. It is likely immunotherapy will be available in the near future as a well tolerated and effective therapy for treating peanut allergy. The use of the anti-IgE therapy in conjunction with other immunotherapy would possibly be the best treatment option in the future.     

Oral immunotherapy for food allergy

Food allergy is a pathological, potentially deadly cascade of immune responses to molecules or molecular fragments that are normally innocuous when encountered in foods, such as milk, egg, or peanut. As the incidence and prevalence of food allergy rise, the standard of care is poised to advance beyond food allergen avoidance coupled with injectable epinephrine treatment of allergen-induced systemic reactions. Recent studies provide evidence that oral immunotherapy may effectively redirect the atopic immune responses of food allergy patients as they ingest small but gradually increasing allergen doses over many months, eliciting safer immune responses to these antigens. Research into the molecular and cellular bases of pathological and therapeutic immune responses, and into the possibilities for their safe and effective modulation, is generating tremendous interest in basic and clinical immunology. We synthesize developments, innovations, and key challenges in our understanding of the immune mechanisms associated with atopy and oral immunotherapy for food allergy.     

Approaches toward peptide-based immunotherapy of autoimmune diseases

Conclusions MHC class II-binding peptides administered in vivo can be effective and selective inhibitors of T cell activation. To selectively interfere with the activation of autoreactive T cells immunotherapy by peptides can be essentially directed to three cellular targets: APC, autoreactive T cells and regulatory T cells. Experimental models of autoimmune diseases have demonstrated that disease can be prevented or treated by peptides acting on each cellular target.The APC can be functionally inactivated by blocking the binding site of MHC class II molecules, thus preventing antigen presentation to T cells. We have demonstrated that injection of a class II-binding peptide can induce MHC class II blockade in vivo [22], resulting in inhibition of class II-restricted T cell activation and of T cell-dependent antibody responses. This is already a validated approach to prevent experimental autoimmune diseases [3, 32] and it may become applicable to the treatment of human autoimmune diseases.The autoreactive T cells could be inactivated by peptide-specific tolerance induction [14, 24], but it is necessary to define all potential autoantigenic epitopes to ensure complete and effective tolerance. Specific inhibition of autoreactive T cells could also be induced by antigen analogues acting as TCR antagonists [15], but this again requires, at a minimum, detailed knowledge of the autoantigen. Regulatory T cells represent a potentially interesting target for selective immunointervention by peptides. The restricted TCR V gene expression by autoreactive pathogenic T cells in some animal models of autoimmune diseases, for example the shared TCR V gene usage characteristic of EAE [1], raises the possibility of controlling self reactivity at the network level, as originally proposed by Cohen and colleagues [9]. Administration of peptides corresponding to TCR sequences utilized by autoreactive T cells has indeed been reported to down-regulate EAE, presumably via induction of anti-idiotypic T cells with suppressive activity [26, 43]. However, this approach does not always result in suppression of encephalitogenic effector T cells, and it may actually lead to enhanced chronic EAE [16]. It is also possible to induce regulatory T cells with suppressive activity by administration of peptides derived from the candidate autoantigen [24, 39] and this specific peptide therapy has been used to prevent the development of autoimmune diabetes in NOD mice [17]. However, if effective tolerance induction requires knowledge of all autoantigenic epitopes, induction of suppressor T cells by antigen is further complicated by our lack of definite molecular explanations for this phenomenon.Therefore, several immunoregulatory mechanisms induced by administration of class II-binding peptides may be responsible, in vivo, for interference with the activation of antigen-specific T cells. Unfortunately, with the possible exception of MHC blockade, the mechanisms involved are far from being clearly understood. What is needed is a more detailed analysis of these mechanisms in experimental autoimmune models to discern the precise mode of action of immunoregulatory peptides. This knowledge may then be applied to the treatment of human autoimmune diseases, keeping in mind that the clinical situation will invariably be even more complex.     

Use of multiple peptides containing T cell epitopes is a feasible approach for peptide-based immunotherapy in Can f 1 allergy

We have previously shown that the major dog allergen Can f 1 contains seven T cell epitope regions, none of which was preferentially recognized. To identify the immune characteristics of Can f 1 epitopes and to verify their suitability for peptide-based allergen immunotherapy, short-term T cell lines were generated with epitope-containing peptides from peripheral blood mononuclear cells of Can f 1 skinprick test-positive allergic and healthy control subjects. The lines were examined for their proliferative capacity and cytokine production upon stimulation with the allergen peptide, a homologous peptide from human tear lipocalin (TL) and Can f 1 and TL proteins. Can f 1 peptides induced proliferation of T cells and gave rise to T cell lines with comparable efficiencies. In particular, the T cell lines of allergic subjects induced with p33-48 and p107-122 favoured the production of interferon-gamma and interleukin-10, respectively. A greater number of Can f 1-specific T cell lines were generated from allergic than from healthy individuals. Two p107-122-induced Can f 1-specific T cell lines also reacted to a homologous peptide of human TL. Our results suggest that several T cell epitope-containing peptides should be used in combination for specific immunotherapy in Can f 1 allergy.     

Liposomes as carriers for allergy immunotherapy

With the aim of obtaining an efficient but safer vaccine for allergy immunotherapy, the possibility of using liposomes as adjuvants has been considered given their proven low toxicity, adjuvant properties and ability to maintain the encapsulated substance in their interior for some time in vivo. Different methods of encapsulating allergenic extracts into neutral, positively, and negatively charged DPPC: cholesterol liposomes have been investigated and the immune response provoked by these in mice was studied and compared to the immune response to free allergen or other adjuvants such as aluminium hydroxide. The results obtained show that allergen encapsulated in all three types of liposomes elicit an increase in specific IgG levels higher than that provoked by free allergen, however, both encapsulation efficiency and specific IgG titre were higher when positively charged (DPPC: cholesterol stearylamine) liposomes were used. Specific IgE levels to allergen in positive and neutral liposomes was lower than to allergen in negative liposomes or adsorbed to Al(OH)3. No difference were found in the behaviour of liposomes prepared by different methods (the results were obtained from pooled sera from different groups of mice so there is no statistical data). These results confirm the immunoadjuvant effect of liposomes for allergy immunotherapy. Further studies to determine their lack of toxicity, pharmacokinetic studies and human clinical studies are necessary to confirm their adequacy for human use and advantage over current immunotherapy methods.     

Rush immunotherapy in a dog with severe ragweed and grass pollen allergy.

BACKGROUND: Forty years of study of naturally occurring IgE-mediated allergy in animals is briefly reviewed. These studies provided models for study of bioactive mediators and innovative pharmacologic therapies for IgE-mediated asthma. Objective: Based on our experience with canine allergy we evaluated and treated a dog with severe grass and ragweed allergy whose allergic dermatitis was uncontrolled by H1 blockers and topical corticosteroids. The dog was miserable during the Chicago grass and ragweed pollen seasons. METHODS: Rush immunotherapy was initiated during the ragweed season of 1997. RESULTS: Dramatic improvement was seen which persisted through the grass and ragweed seasons of 1998 after maintenance immunotherapy. CONCLUSION: The case is presented not as a model for canine immunotherapy but as an example of how animal research can be of value to both animals and humans.     

Food allergy immunotherapy: Oral immunotherapy and epicutaneous immunotherapy

IgE-mediated food allergy remains a significant and growing problem across the globe. Of the various treatment modalities, oral immunotherapy (OIT) and epicutaneous immunotherapy (EPIT) have been the best studied. Across various studies of OIT for egg, milk, and peanut allergy, strong levels of desensitization have been shown. With egg and peanut OIT, a limited remission, or sustained unresponsiveness (SU), has further been demonstrated. These advances have been further validated by successful phase 2 and phase 3 studies of peanut OIT. EPIT, using daily administrations of a proprietary patch, demonstrated efficacy as well as safety and tolerability in parallel phase 2 studies; however, its phase 3 study did not meet its primary efficacy outcome. Despite its good track record of desensitization, the safety and tolerability of OIT has remained a question. EPIT, on the other hand, has proven safe and tolerable; however, the adequacy of its desensitization has remained to be determined. As OIT and EPIT continue their march toward regulatory review, optimizations for immunotherapy and novel therapies continue to be developed providing hope for food allergy patients everywhere.     

Prospects for immunotherapy of malignant disease

The majority of T cell-recognized tumour antigens in humans are encoded by genes that are also present in normal tissues. Low levels of gene expression in normal cells can lead to the inactivation of high-avidity T cells by immunological tolerance mechanisms. As a consequence, low-avidity T cell responses in patients are often inadequate in providing tumour protection. Recently, several technologies have been developed to overcome tolerance, allowing the isolation of high-affinity, HLA-restricted receptors specific for tumour-associated peptide epitopes. Furthermore, transfer of HLA-restricted antigen receptors provides an opportunity to empower patient T cells with new tumour-reactive specificities that cannot be retrieved from the autologous T cell repertoire.     

Recombinant allergen and peptide-based approaches for allergy prevention by oral tolerance

Several studies conducted in animal models for immunologically-mediated hypersensitivity diseases have shown that oral administration of antigens early in life can prevent the development of specific humoral and cellular immune responses and thus hypersensitivity reactions to the respective antigens. Such data were also obtained in models for Immunoglobulin E (IgE)-associated allergy, the most common hypersensitivity disease affecting more than 25% of the population. Based on data obtained in animal models for allergy several clinical intervention studies have been conducted in children to study if oral administration of materials containing allergens or allergen-derived peptides early in life can prevent the subsequent development of allergy. In this article we argue that oral tolerance induction could be a potent way to prevent allergy and may be even improved regarding efficacy provided that well-defined allergen molecules and/or allergen-derivatives were used in optimized dose regimens and periods of intervention. The knowledge regarding the molecular and immunological characteristics of allergens which has been achieved in the last decades is a prerequisite for such a treatment. In fact, defined recombinant allergens/allergen derivatives and allergen-derived synthetic peptides from the most common allergen sources are now available for targeted intervention. Moreover, molecular allergy diagnosis allows deciphering the disease-causing relevant allergens for different regions in the world allowing composing cocktails of tolerogens according to the needs of populations from different parts of the world. Furthermore, it is suggested to use defined allergen molecules and epitopes in the analysis of clinical tolerance studies. This will allow understanding if clinical unresponsiveness is due to true immunological tolerance or to other mechanisms such as induction of blocking antibodies or cellular immunomodulation. Using molecularly defined tolerogens it can now be explored if oral tolerance induction is a powerful strategy to prevent IgE-associated allergy.     

Breast cancer immunotherapy: monoclonal antibodies and peptide-based vaccines

Recently, immunotherapy has emerged as a treatment strategy in the adjuvant setting of breast cancer. In this review, monoclonal antibodies in passive and peptide-based vaccines, as one of the most commonly studied in active immunotherapy approaches, are discussed. Trastuzumab, a monoclonal antibody against HER-2/neu, has demonstrated considerable efficacy. However, resistance to trastuzumab has led to development of many targeted therapies which have been examined in clinical trials. Monoclonal antibodies against immune-checkpoint molecules that are dysregulated by tumors as an immune resistance mechanism are also explained in this review. Additionally, monoclonal antibodies with the ability to target breast cancer stem cells that play a role in cancer recurrence are mentioned. Here, clinical trials of HER-2/neu B and T cells, MUC1 and hTERT cancer peptide vaccines are also presented. In addition, various strategies for enhancing vaccine efficacy including combination with monoclonal antibodies and using different delivery systems for peptide/protein-based vaccine are described.     

Determinant spreading and tumor responses after peptide-based cancer immunotherapy

Modern immunological assays are very sensitive for detection of antigen-specific T cells. These assays are used to detect increased levels of T cells after peptide-based immunotherapy for cancer in an attempt to describe surrogate endpoints correlated with anti-tumor activity. Recent reports demonstrate that determinant spreading develops in a high frequency of subjects with tumor regression responses after this type of immunotherapy and could be valuable for trial monitoring and the design of more effective vaccines.     

Classic specific immunotherapy and new perspectives in specific immunotherapy for food allergy

Food allergy is a major cause of life-threatening hypersensitivity reactions. Food-induced anaphylaxis is the most common reason for someone to present to the emergency department for an anaphylactic reaction. The avoidance of the allergenic food is the only method of preventing further reactions that is currently available for sensitized patients. Strict avoidance of specific foods is the accepted treatment of food-induced allergic reactions but is often an unrealistic therapeutic option for food-induced hypersensitivity reactions for the many reasons previously described. Desirable therapeutic strategies for the treatment and prevention of food allergies must be safe, relatively inexpensive and easily administered. Recent advances in the understanding of the immunological mechanisms underlying allergic disease and better characterization of food allergens have greatly expanded the potential therapeutic options for future use. Several different forms of immunomodulatory therapies are currently under investigation: peptide immunotherapy, mutated protein immunotherapy, allergen DNA immunization, vaccination with immunostimulatory DNA sequences and anti-immunoglobulin E (Anti-IgE) therapy.