Adjuvants in allergen-specific immunotherapy: modulating and enhancing the immune response

Allergen-specific immunotherapy (AIT) is the only treatment that can affect the natural course of allergic diseases such as allergic asthma, allergic rhinitis, and IgE-mediated food allergy. Adjuvants are used to induce a quicker, more potent, and longer-lasting immune response. Only 4 compounds are used as adjuvants in currently marketed AIT products: aluminum hydroxide, calcium phosphate, microcrystalline tyrosine (MCT), and monophosphoryl lipid A (MPL). The first 3 adjuvants are delivery systems with a depot effect, although they may also have immunomodulatory properties. These first-generation adjuvants are still widely used, especially aluminum hydroxide. However, aluminum is subject to limitations. MCT is the depot formulation of L-tyrosine; it enhances IgG production without inducing a significant increase in IgE, is biodegradable, and has good local and systemic tolerability. In turn, MPL is an immunostimulatory agent that is the only second-generation adjuvant currently used for AIT. In addition, multiple adjuvants are currently being studied, including immunostimulatory sequences (ISSs), nanoparticles (liposomes, virus-like particles, and biodegradable polymers), and phosphatidylserine derivatives. In a murine model of allergic bronchial inflammation by sensitization to olive pollen, the specific IgE level was significantly higher in sensitized mice treated with olive pollen and aluminum hydroxide. However, specific IgE levels were significantly reduced and bronchial hyperreactivity significantly improved in sensitized mice treated with olive pollen and bacterial derivatives (MPL or ISSs)

La inmunoterapia específica con alérgenos (ITE) es el único tratamiento con potencial para modificar la evolución natural de enfermedades alérgicas como el asma alérgica, la rinitis alérgica y la alergia a alimentos mediada por IgE. Los adyuvantes se usan para provocar una respuesta inmune más rápida, más potente y de mayor duración. Hasta ahora, solo cuatro compuestos se usan como adyuvantes en los productos de ITE comercializados actualmente: hidróxido de aluminio, fosfato cálcico, tirosina microcristalina (MCT) y monofosforil lípido A (MPL). Los tres primeros son sistemas de liberación retardada (efecto depot), aunque también podrían tener propiedades inmunomoduladoras. Estos adyuvantes de primera generación todavía se usan ampliamente, sobre todo el hidróxido de aluminio. Sin embargo, el aluminio tiene algunas limitaciones. MCT es la formulación de liberación retardada de la L-tirosina; aumenta la producción de IgG sin provocar un incremento significativo de IgE, es biodegradable y tiene una buena tolerabilidad local y sistémica. A su vez, MPL es un inmunoestimulador y es el único adyuvante de segunda generación usado actualmente en ITE. Además, hay múltiples adyuvantes en investigación, como las secuencias inmunoestimuladoras (SIE), nanopartículas (liposomas, partículas similares a virus y polímeros biodegradables) y derivados de la fosfatidilserina.En un modelo múrido de inflamación bronquial alérgica por sensibilización al polen de olivo, el nivel de IgE específica fue significativamente mayor en los animales sensibilizados tratados con polen de olivo e hidróxido de aluminio. Sin embargo, en los animales sensibilizados tratados con polen de olivo y derivados bacterianos (MPL o SIE) se observó una disminución significativa del nivel de IgE específica y una mejoría significativa de la hiperreactividad bronquial

Efficacy of high-dose sublingual immunotherapy in children allergic to house dust mites in real-life clinical practice.

BACKGROUND: The aim of the study was to evaluate the efficacy and safety of high-dose mite sublingual immunotherapy (SLIT) administered in children with allergic rhinitis in real-life clinical practice. Moreover, we analysed the clinical course of asthma severity. METHODS: Retrospective, observational, monocentre study. Medical records of patients treated between 2001 and 2008 were reviewed. Patients received a standardised Dermatophagoides pteronyssinus+Dermatophagoides farinae extract (300 IR/ml) manufactured by Stallergenes (Staloral(®) 300). Patients were evaluated before SLIT initiation and at 6, 12, 24, 36 and 48 months. Global assessment of SLIT efficacy was measured using a visual analogue scale (VAS) and a rhinitis medication consumption score (RMCS). A global asthma score was used to estimate the clinical course of asthma severity. RESULTS: We obtained data from 78 patients, 43.6% male. The mean (± SD) age was 11.0 ± 3.0 years. Most patients (69.2%) suffered from allergic rhinitis plus asthma. Patient evaluation of allergy severity (VAS) revealed a highly significant improvement between baseline and six months (p < 0.001, Wilcoxon test): 4.0 ± 1.7 cm vs. 7.3 ± 4.6 cm. This improvement was maintained throughout the four-year follow-up period. The use of medications (RMCS) was significantly reduced in the first six months (4.6 ± 2.5 points at baseline vs. 0.8 ± 1.6 points at six months visit, p < 0.001, Wilcoxon test) and remained very low until the end of follow-up. We did not find a temporal improvement in asthma severity. CONCLUSIONS: This retrospective study indicates that high-dose SLIT in children with rhinitis caused by house dust mites is well-tolerated and could be an effective treatment.

Tolerance and short-term effect of a cluster schedule with pollen-extracts quantified in mass-units

We performed a prospective, multicenter study to assess the tolerance and possible short-term effects of allergen vaccines administered according to a cluster schedule in the months immediately preceding the onset of the pollen season. The study was carried out in eight centers and included 191 patients (children and adults) with allergic respiratory disease due to sensitization to olive tree and/or grass pollen. Of these, 34 patients acted as controls and the remaining patients received immunotherapy administered in the initiation phase according to a cluster schedule of eight doses injected on four visits. After 3 months of treatment, significant differences were found between the two groups in medication consumption (antihistamines in drops and oral formulations: p = 0.045 and p = 0.001, respectively; short-acting β2-agonist treatments: p = 0.004) and respiratory symptoms (wheezing and coughing: p = 0.035 and 0.014, respectively). The cytokine profile (interleukin [IL]-4, 5, 10 and 2, interferon [IFN-γ], and tumor necrosis factor [TNF-α]) was determined before the start of treatment and at the end of follow-up (4-5 months). Levels of IL-4, 5 and 10 (Th2 profile) decreased while those of IL-2, IFN-γ, and TNF-α (Th1 profile) decreased. These differences were more marked in the active group than in the control group but were not statistically significant. No severe adverse effects were recorded. This study shows that the schedule tested had an acceptable tolerance profile and produced significant changes in symptom and medication scores after a few months of treatment. A double-blind, placebo-controlled study is needed to confirm these results (AU)

Se ha llevado a cabo un estudio prospectivo y multicéntrico con el objetivo de valorar la tolerancia y posible efecto a corto plazo de las vacunas alergénicas administradas bajo pauta cluster en los meses inmediatamente anteriores al inicio de la estación polínica. El estudio se realizó en 8 centros, incluyéndose un total de 191 pacientes (niños y adultos) con enfermedad alérgica respiratoria por sensibilización a polen de olivo y/o gramíneas. De ellos, 34 actuaron como controles y a los pacientes restantes se les administró inmunoterapia bajo una pauta cluster, en la fase de iniciación, de 8 dosis administradas en 4 visitas. Tras 3 meses de tratamiento, se registraron diferencias significativas entre ambos grupos en el consumo de medicación (antihistamínicos en colirio y orales -p = 0,045 y p = 0,001 respectivamente- y ß2 de corta duración -p = 0,004-) así como en síntomas pulmonares (sibilancias y tos -p = 0,035 y 0,014 respectivamente-). Por otro lado, se determinó el perfil de citocinas (IL-4, 5, 10 y 2, IFN-gamma y TNF-a) de forma previa al inicio del tratamiento y al finalizar el seguimiento (4-5 meses). Se observaron descensos en los niveles de IL-4, 5 y 10 (perfil TH2) y aumento en los valores de IL-2, IFN-gamma y TNF-a (perfil TH1), más marcados en el grupo activo que en el control, sin alcanzar significación estadística. No se registraron efectos adversos severos. Por tanto, podemos observar que la pauta ensayada mostró un adecuado perfil de tolerancia, y tras pocos meses de tratamiento se registraron cambios significativos en la puntuación de síntomas y medicación, siendo necesaria la realización de un estudio con un diseño doble ciego frente a placebo para confirmar los resultados obtenidos (AU)