Mechanisms of desensitization with oral immunotherapy and epicutaneous immunotherapy.

Background: Oral immunotherapy (OIT) and epicutaneous immunotherapy (EPIT) are emerging therapies for food allergy. With several recently published exploratory trials and randomized controlled clinical trials that support these procedures, there is a clear progress and interest toward making these treatment options available for allergist/immunologists and patients with food allergies entrusted to their care. However, there still remain many questions and concerns to be addressed before these procedures can be fully understood. Objective: The purpose of the present report is to trace some of the important historical milestones in the development of OIT and EPIT that have contributed to their evolving clinical application to the treatment of food allergy, to describe some of the current understandings of the immunologic mechanisms by which these procedures elicit desensitization, and to provide some areas for future inquiry and research. Methods: An extensive research was conducted in the medical literature data bases by applying terms such as food allergy, desensitization, tolerance, unresponsiveness, Treg cells, allergen immunotherapy (AIT), oral immunotherapy (OIT), and epicutaneous immunotherapy (EPIT). Results: OIT and EPIT take their origins from AIT (also called desensitization), a procedure first reported for the treatment of hay fever over a 100 years ago in which slowly increasing doses of a specifically relevant allergen were administered until a maintenance dosage was achieved when the patient was free of symptoms. OIT and EPIT differ from AIT in certain aspects including the route of administration of the allergen as well as their relative shorter period of sustained unresponsiveness. Conclusion: The origins and important historical landmarks that have been made in the field of food allergy immunotherapy are presented in the context of the immunologic mechanisms that contribute to the pathogenesis of these disorders. Although considerable progress has been made in recent years toward making these treatment options available for allergist/immunologists and patients with food allergies, there still remain many questions and concerns to be addressed before these procedures can be fully understood, which can be illuminated by future research.

Prevention of EAE by tolerogenic vaccination with PEGylated antigenic peptides.

BACKGROUND: Therapeutic treatment options for chronic autoimmune disorders such as multiple sclerosis (MS) rely largely on the use of non-specific immunosuppressive drugs, which are not able to cure the disease. Presently, approaches to induce antigen-specific tolerance as a therapeutic approach; for example, by peptide-based tolerogenic 'inverse' vaccines have regained great interest. We have previously shown that coupling of peptides to carriers can enhance their capacity to induce regulatory T cells in vivo. METHOD: In this present study, we investigated whether the tolerogenic potential of immunodominant myelin T-cell epitopes can be improved by conjugation to the synthetic carrier polyethylene glycol (PEG) in an experimental autoimmune encephalomyelitis (EAE) mouse model for chronic MS (MOG C57BL/6). RESULTS: Preventive administration of the PEGylated antigenic peptide could strongly suppress the development of EAE, accompanied by reduced immune cell infiltration in the central nervous system (CNS). Depletion of regulatory T cells (Tregs) abrogated the protective effect indicating that Tregs play a crucial role in induction of antigen-specific tolerance in EAE. Treatment during the acute phase of disease was safe and did not induce immune activation. However, treatment at the peak of disease did not affect the disease course, suggesting that either induction of Tregs does not occur in the highly inflamed situation, or that the immune system is refractory to regulation in this condition. CONCLUSION: PEGylation of antigenic peptides is an effective and feasible strategy to improve tolerogenic (Treg-inducing) peptide-based vaccines, but application for immunotherapy of overt disease might require modifications or combination therapies that simultaneously suppress effector mechanisms.

The role of IL-25 in the reduction of oxidative stress and the apoptosis of airway epithelial cells with specific immunotherapy in an asthma mouse model.

Oxidative stress and cell apoptosis play important roles in the pathogenesis of asthma. Specific immunotherapy (SIT) is the only curative approach for asthma and is effective at decreasing asthmatic oxidation and cell apoptosis, but the mechanisms remain unclear. In this study, by using in vivo and in vitro models, we indirectly demonstrated that SIT alleviated the apoptosis and oxidative stress of bronchial epithelial cells in an asthma model through regulating interleukin (IL)-25. Female BALB/c mice were used for an asthma model induced by exposure to house dust mite (HDM) extracts as allergens. Prior to the challenge, the mice were either given the SIT vaccine or N-Acetyl-L-cysteine (NAC). RESULTS: Compared with that in asthma models, SIT administration decreased (1) airway hyper-responsiveness; (2) the production of cytokines, including IL-4, IL-5, IL-13, and IL-25, as well as serum HDM-specific IgE and IgG1, as shown by ELISA; and (3) lipid oxidative species, such as reactive oxidative species (ROS) and malondialdehyde (MDA), in the lung tissue. Moreover, TUNEL staining showed that SIT alleviated pulmonary cell apoptosis. In vitro, flow cytometry showed that human recombinant IL-25 (rIL-25) led to increased cell apoptosis and ROS in the human epithelial cell line 16HBE in a dose and time-dependent fashion. In conclusion, in vivo, SIT reduced asthmatic Th2 cytokine levels and the production of IL-25 and alleviated oxidative stress and cell apoptosis in the lung tissue. In vitro, IL-25 increased the number of apoptotic cells and the production of ROS in16HBE cells.

Depigmented-polymerized mixed grass/birch pollen extract immunotherapy is effective in polysensitized patients.

BACKGROUND: Although many patients with allergic rhinoconjunctivitis have symptoms due to sensitization with more than one pollen allergen, and mixed pollen extracts are widely used for allergen immunotherapy in practice, there are few published trials. METHODS: We performed a 2-year multicentre, double-blind, placebo-controlled trial of subcutaneous immunotherapy with mixed depigmented-polymerized birch and grass pollen extract in 285 patients with allergic rhinoconjunctivitis symptomatic during both birch and grass pollen seasons. Primary outcome was combined symptom and medication score (SMS) assessed by daily visual analogue scales (VAS). Analysis included a placebo-based analysis examining the effect of treatment only on days when placebo patients were symptomatic. RESULTS: There was a significant reduction in median SMS for actively treated patients (median 5.70 (interquartile range 2.62-10.02) compared with 7.07 (3.47-10.71) for placebo, P = 0.0385). Rhinitis quality-of-life scores were significantly better for active compared with placebo, and other secondary endpoints were not significantly different. Placebo-based analysis showed a 33.7% reduced SMS at year 2 for active treatment compared with placebo on days when placebo patients were symptomatic. Both birch pollen- and grass pollen-specific IgG4 increased with active treatment. CONCLUSIONS: This study shows efficacy of mixed pollen extracts for immunotherapy for patients symptomatic to both birch and grass pollen allergens. The relatively modest effect may reflect 50% dose reduction for each allergen in the mixture. It supports VAS for symptom assessment and placebo-based analysis as useful for the analysis of immunotherapy trials. The safety of modified extracts may allow study of mixed extracts without dose reduction to improve efficacy.

Bronchial allergen provocation: a useful method to assess the efficacy of specific immunotherapy in children.

BACKGROUND: The clinical efficacy of subcutaneous allergen-specific immunotherapy (SCIT) varies between patients. New preparations are under development, and an objective tool with which to evaluate their efficacies in individual patients has become necessary. Our primary research question is whether bronchial allergen provocation (BAP) can be used to assess the efficacy of SCIT. METHODS: In 42 house dust mite (HDM) allergic children (average age: 8.6 yr) with asthma, we analysed the clinical and objective improvements of a standardised HDM allergoid. All patients underwent two BAPs, one before SCIT and another 1 yr after SCIT. Fourteen patients who were recommended but chose not to undergo SCIT represented the control group. The total and specific IgE were analysed before SCIT; in addition, after SCIT, specific IgG and IgG4 were analysed. RESULTS: After SCIT, the patients' allergen-specific bronchial hyper-reactivity (BHR) was significantly improved; specifically, their PD(20) FEV(1) was 34.4 AU before and 63.3 AU after SCIT (p < 0.01). The PD(20) FEV(1) of the control group remained unchanged. Although BHR improved significantly in the treatment group, we were able to differentiate between the responders (n = 17, 60.7%) and non-responders (n = 11, no improvement in BAP). The patients in both groups stated that SCIT had led to a subjective improvement in their symptoms, in contrast to the untreated control group, but only the responders required less medication after SCIT (p < 0.01). CONCLUSIONS: After 1 yr of SCIT against HDM, 60.7% of the patients observed in this study exhibited significant improvements, as defined by BAP. However, BAP was also able to identify the non-responders to treatment. Thus, BAP is a useful and objective method of estimating the effectiveness of SCIT and is not influenced by a placebo effect.