Preventive actions of allergen immunotherapy: the facts and the effects in search of evidence

Allergen immunotherapy (AIT) is the only treatment that works on the causes of allergy. Available AIT nowadays are subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) for allergic rhinitis and asthma, while for allergy to Hymenoptera venom only subcutaneous route is recommended. A bulk of trials and meta-analyses demonstrated that efficacy and safety of AIT in decreasing allergic clinical symptoms and use of rescue medications, while its preventive capacity is yet under investigation. The most important of these effects is the prevention of potentially fatal anaphylactic reactions to Hymenoptera stings by venom immunotherapy (VIT). A certain number of studies thus far available showed that AIT, in both forms, is able to prevent the progress of allergic rhinitis into asthma and the development of new sensitizations. These effects should be related to the mechanisms of action of AIT. In fact, it has been demonstrated that both SCIT and SLIT are able to modify the allergen presentation by dendritic cells, with result in modification of the phenotype of allergen-specific T cells, switching from the typical of allergic inflammation Th2-type response to a Th1-type one. Also allergen-specific T regulatory (Treg) cells play a pivotal role by producing suppressive cytokines, such as IL-10 and TGF-beta. However, the only plain evidence of a preventive effect concerns VIT, while the other outcomes need to be furtherly investigated.     

A critical appraisal on AIT in childhood asthma

Abstract

Allergen immunotherapy (AIT) is the only disease-modifying treatment approved for allergic rhinitis and allergic asthma and represents a suitable therapeutic option, especially in childhood, to modify the progression of respiratory allergic diseases. Starting from the previous “generic class effect” evaluation, as testified by the numerous meta analyses, AIT is now considered a product-specific pathogenic-oriented treatment.

Background

AIT was empirically proposed more than one century ago in the subcutaneous form (SCIT), but the IgE-mediated mechanism of allergy was elucidated only after 50 years of clinical use of the treatment. The sublingual administration (SLIT) was developed during the 1980 ties, to achieve an improvement in safety and convenience. While SCIT is approved in the United States for the treatment of asthmatic patients with more than 12 years, so far few trials evaluated the clinical efficacy and safety of SLIT in children with allergic asthma, although the indications and some aspects remain unclear. Certainly, due to compliance problems, the age below 3 years may be reasonably considered a practical contraindication.

Conclusions

Given that some specific AIT products are effective and approved as drugs (AIFA, EMA, FDA), the use in children is still debated. Some aspects still need robust confirm: (a) the safety of AIT in asthma; (b) the optimal regimen of administration; (c) the role of AIT as preventative treatment for asthma development.

     

Sublingual immunotherapy provides an early increase of interferon-gamma production

Allergic rhinitis (AR) is characterized by Th2 polarized immune response. Allergen-specific subcutaneous immunotherapy may restore a physiologic Th1 profile. However, there are few studies investigating the immunological effects of sublingual immunotherapy (SLIT). The aim of this study is to investigate whether a pre-seasonal SLIT course could affect IFN-gamma production. Forty-four AR patients with pollen allergy assumed pre-seasonal SLIT for 3 months. IFN-gamma-specific producing cells were assessed by cytokine ELISPOT before and 3 months after the beginning of SLIT. Visual analogue scale (VAS) for symptoms and medication score was also evaluated. The frequency of IFN-gamma-specific producing cells significantly increased after SLIT (p<0.01), and this increase was significantly associated with improvement of both symptoms (p<0.001) and medication use (p<0.01). In conclusion, these results may be considered clinically relevant as SLIT treatment may induce a quick IFN- gamma response that is related to clinical improvement.     

Cluster Subcutaneous Allergen Specific Immunotherapy for the Treatment of Allergic Rhinitis: A Systematic Review and Meta-Analysis

Background

Although allergen specific immunotherapy (SIT) represents the only immune- modifying and curative option available for patients with allergic rhinitis (AR), the optimal schedule for specific subcutaneous immunotherapy (SCIT) is still unknown. The objective of this study is to systematically assess the efficacy and safety of cluster SCIT for patients with AR.

Methods

By searching PubMed, EMBASE and the Cochrane clinical trials database from 1980 through May 10th, 2013, we collected and analyzed the randomized controlled trials (RCTs) of cluster SCIT to assess its efficacy and safety.

Results

Eight trials involving 567 participants were included in this systematic review. Our meta-analysis showed that cluster SCIT have similar effect in reduction of both rhinitis symptoms and the requirement for anti-allergic medication compared with conventional SCIT, but when comparing cluster SCIT with placebo, no statistic significance were found in reduction of symptom scores or medication scores. Some caution is required in this interpretation as there was significant heterogeneity between studies. Data relating to Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) in 3 included studies were analyzed, which consistently point to the efficacy of cluster SCIT in improving quality of life compared to placebo. To assess the safety of cluster SCIT, meta-analysis showed that no differences existed in the incidence of either local adverse reaction or systemic adverse reaction between the cluster group and control group.

Conclusion

Based on the current limited evidence, we still could not conclude affirmatively that cluster SCIT was a safe and efficacious option for the treatment of AR patients. Further large-scale, well-designed RCTs on this topic are still needed.     

How to fit allergen immunotherapy in the elderly

Asthma, allergic rhinitis (AR) and atopic dermatitis are very common in young people, but in the latest decades it was increasingly recognized that also individuals of higher ages, including the population over 65 years, are concerned. Actually, it is now acknowledged the aging does not considerably alter the immune response to allergens. Allergen immunotherapy (AIT) is the only treatment that works on the causes of allergy, but elderly people are commonly excluded from AIT, except the cases of insect sting allergy. A number of recent studies showed that aged individuals also successfully respond to AIT for respiratory allergy. Therefore, there is no reason to exclude elder patients from AIT. Anyhow, clinical conditions that are considered absolute or relative contraindications are quite frequent in this aged population, thus the risk/benefit ratio must be carefully evaluated for each patient, taking into account that the more frequent occurrence of co-morbidities and the consequent need of daily-based multidrug regimen can favor adverse effects. An important issue concern the ability of AIT, and particularly of sublingual immunotherapy, to significantly improve the quality of life, that often is particularly impaired in the elderly, reducing symptoms and drugs consumption.     

Formulation and in-vitro characterization of fast-disintegrating herbal extract sublingual immunotherapy tablet for peanut-induced allergic asthma

BackgroundAllergen immunotherapy (AIT) involves the regimen of gradually incrementing doses of the allergen, thereby inducing desensitization and tolerance. Sublingual Immunotherapy tablets (SLIT-tablets) have been formulated for several allergies and had manifested efficacy for allergic rhinitis and allergic asthma. SLIT promises an alternative method to other routes of AIT enabling patients to self-administer AIT.ObjectiveThe study aimed to formulate fast disintegrating SLIT containing crude peanut extract for peanut-induced allergic asthma.MethodsThe crude peanut extract was prepared by a simple extraction method and was subjected to quantitative and qualitative analysis. The extract was also characterised for its physical properties. The preformulation study for the extract and excipients of the tablet was performed using FT-IR spectroscopy and Differential scanning calorimetry. The tablet powder blends were characterised for pre-compression properties. The SLIT tablets were developed by direct compression and the post-compression evaluation was performed.ResultsThe results of the quantitative and qualitative analysis of extract confirmed the presence of peanut proteins in the extract. The preformulation studies using FT-IR spectroscopy and Differential Scanning Calorimetry revealed that there is no significant interaction between the CPE and excipients. The pre-compression characterisation showed that the powder blends had good flowproperties. Three doses of SLIT tablets were formulated with each dose containing four batches and the tablet of each dose was optimized by studying the effect of varying concentrations of super disintegrants on disintegration time and dissolution rate. The post compression characterization of the tablets was performed and the optimized batch of the three doses with the concentration of 5% crospovidone and 2% croscarmellose sodium showed less wetting time and high-water absorption ratio, shorter disintegration time of 14secs and maximum drug release of >90% within 2–3 min.ConclusionThe results indicated the suitability of formulated SLIT tablets for peanut induced allergic asthma.     

Serum IL-4 as a marker of immunological response to sublingual immunotherapy

Allergic rhinitis (AR) is characterized by a Th2 polarized immune response. Specific Immunotherapy modifies this bias restoring a physiologic Th1 profile. Sublingual immunotherapy (SLIT) is widely prescribed, but there is no early, simple marker of response. This study was undertaken in order to determine whether serum IL-4 might be a possible marker of SLIT immunological response in order to quickly and easily detect responder patients. Thirty-nine AR patients with a pollen allergy assumed preseasonal SLIT for 3 months. VAS for symptoms and medication efficacy were evaluated. Serum IL-4 was assessed before and 3 and 6 months after SLIT initiation. Eighty-two percent of patients (32/39) showed a clinical response to SLIT. Serum IL-4 significantly decreased at 6 months post-therapy in responders, whereas it increased in non-responders. In conclusion, these results may be considered clinically relevant proof that SLIT treatment induces a quick reduction in Th2 polarization. Serum IL-4 appears to be an early marker of immunological response to SLIT.     

Serum IL-9 levels and sublingual immunotherapy: preliminary report

Th9 is a new T cell subset characterized by IL-9 production. It has been reported that serum IL-9 levels are related with symptom severity in patients with allergic rhinitis (AR). This study is aimed at investigating whether serum IL-9 may be modulated by sublingual immunotherapy (SLIT) in patients with persistent AR due to Parietaria allergy. Twenty-one AR patients (9 males, median age 41 years) successfully treated with SLIT and 52 AR patients (25 males, median age 34 years) treated only with drugs were evaluated during the pollen season. Serum IL-9 was dosed in all patients. SLIT-treated patients showed significantly lower serum IL-9 levels than untreated AR patients (p <0.0001). In conclusion, this preliminary study shows that a single pre-seasonal SLIT course might modulate serum IL-9.     

Effects of specific allergen immunotherapy on biological markers and clinical parameters in asthmatic children: a controlled-real life study

Background

Allergen-specific immunotherapy (AIT) is the only treatment able to change the natural course of allergic diseases. We aimed at investigating the clinical efficacy of SLITOR (Serbian registered vaccine for sublingual allergen specific immunotherapy).

Methods

7–18 years old children with allergic asthma and rhinitis were enrolled and addressed to the active (AIT plus pharmacological treatment) or control (standard pharmacological treatment only) group. Clinical and medications scores, lung function and exhaled FeNO were measured at baseline and at every follow-up.

Results

There was a significant improvement in both nasal and asthma symptom scores as well as in medication score in SLIT group. SLIT showed an important influence on lung function and airway inflammation.

Conclusions

Our data showed that SLITOR was effective not only in terms of patient reported outcomes but an improvement of pulmonary function and decrease of lower airway inflammation were also observed.

     

An update on the pharmacoeconomics of antifungal pharmacotherapy

The incidence and severity of invasive fungal infections are on the rise and they pose a risk of significant morbidity and mortality. The cost burden of fungal infections in the United States is high. There are many newer, less toxic antifungal agents to manage these challenging infections; however, these agents also carry a high cost of their own. When considering an antifungal agent for a specific patient, it is important to consider safety, efficacy, and cost, thus making it essential to continually evaluate the antifungal pharmacoeconomic literature to assist in the therapeutic decision-making process for patients with invasive fungal infections. Unfortunately, there is a lack of pharmacoeconomic studies addressing the costs associated with the treatment and prevention of fungal infections. Future large-scale clinical studies should include pharmacoeconomic analyses and end points that encompass all costs associated with antifungal drug use, not solely drug acquisition costs.     

Immune response to sublingual immunotherapy in children allergic to mites

Allergic rhinitis (AR) is characterized by Th2 polarized immune response. Specific immunotherapy modifies this arrangement restoring a physiologic Th1 profile. Sublingual immunotherapy (SLIT) is widely prescribed, but there is no early marker of response. The aim of this study is to investigate possible marker of SLIT effectiveness. Thirty children with mite allergy were studied: 15 were treated with drugs alone, 15 with SLIT and drugs on demand. The study lasted 2 years. Visual analogue scale (VAS) for symptoms and medication score were evaluated. Serum cytokines (IL-2, IL-4, IL-6, IL-8, IL-10, IFN-gamma, MCP-1, and TNF-alpha) were assessed by ELISA before and after 1 and 2 year SLIT. SLIT-treated children obtained a significant improvement of symptoms and a reduction of drug use, whereas children treated with a drug alone did not obtained any change. IL-10 significantly increased, whereas Th2-dependent and pro-inflammatory cytokines significantly decreased. In conclusion, the present study demonstrates that 2-year SLIT is capable of inducing immunologic hyporeactivity to mites.     

Lymphokine-activated killer cell adoptive immunotherapy for cancer treatment and its significance]

New culture system, CDCS-T1, was developed for clinical conduction of lymphokine-activated killer (LAK) cell adoptive immunotherapy (AIT). Advanced or recurrent cancer patients of digestive tract were treated with AIT with LAK cells generated by CDCS-T1 in combination with plasma exchange. Partial responses were shown in 10 to 20% of patients treated. Long survival was found in some responders, indicating the significance of LAK therapy for cancer treatment. AIT with LAK cell transfer was also conducted in patients with esophageal cancer as postoperative adjuvant therapy. Better restoration of postoperative depression of immunological parameters was found in patients with postoperative LAK cell transfer. It is suggested that postoperative LAK cell transfer is a good candidate for adjuvant immunotherapy for cancer treatment.     

Sublingual Immunotherapy as an Alternative to Induce Protection Against Acute Respiratory Infections

Sublingual route has been widely used to deliver small molecules into the bloodstream and to modulate the immune response at different sites. It has been shown to effectively induce humoral and cellular responses at systemic and mucosal sites, namely the lungs and urogenital tract. Sublingual vaccination can promote protection against infections at the lower and upper respiratory tract; it can also promote tolerance to allergens and ameliorate asthma symptoms. Modulation of lung’s immune response by sublingual immunotherapy (SLIT) is safer than direct administration of formulations by intranasal route because it does not require delivery of potentially harmful molecules directly into the airways. In contrast to intranasal delivery, side effects involving brain toxicity or facial paralysis are not promoted by SLIT. The immune mechanisms underlying SLIT remain elusive and its use for the treatment of acute lung infections has not yet been explored. Thus, development of appropriate animal models of SLIT is needed to further explore its potential advantages. This work shows how to perform sublingual administration of therapeutic agents in mice to evaluate their ability to protect against acute pneumococcal pneumonia. Technical aspects of mouse handling during sublingual inoculation, precise identification of sublingual mucosa, draining lymph nodes and isolation of tissues, bronchoalveolar lavage and lungs are illustrated. Protocols for single cell suspension preparation for FACS analysis are described in detail. Other downstream applications for the analysis of the immune response are discussed. Technical aspects of the preparation of Streptococcus pneumoniae inoculum and intranasal challenge of mice are also explained.SLIT is a simple technique that allows screening of candidate molecules to modulate lungs’ immune response. Parameters affecting the success of SLIT are related to molecular size, susceptibility to degradation and stability of highly concentrated formulations.     

Epigenetic inactivation of SLIT2 in human hepatocellular carcinomas

Recent findings have shown that SLIT2 appears to function as a novel tumor suppressor gene. In addition, hypermethylation of its promoter region has been detected in various cancers, including breast and lung cancer, colorectal carcinoma, and gliomas. Here, we report for the first time that there is epigenetic silencing of SLIT2 in human hepatocellular carcinoma (HCC). Downregulation of SLIT2 was detected in 6 of 8 (75%) HCC cell lines by quantitative real-time RT-PCR (qRT-PCR), and the downregulation of SLIT2 was generally dependent on the degree of methylation at the promoter region. Furthermore, expression of SLIT2 was restored in relatively low-expressing cell lines after treatment with 5-aza-2-deoxycytidine (5-Aza-dC). Downregulation of SLIT2 expression was also detected in 45 of 54 primary HCC samples (83.3%), and the decrease in expression was significantly correlated with CpG island hypermethylation. This decrease of SLIT2 expression was also associated with lymph node metastasis in HCC. Moreover, overexpression of SLIT2 in SMMC-7721 cells induced by recombinant adenovirus suppressed cell growth, migration, and invasion, These results suggest that epigenetic inactivation of SLIT2 in HCC may be important in the development and progression of HCC. Thus, SLIT2 may be useful as a therapeutic target in the treatment of HCC.     

舌下特异性免疫治疗变应性鼻炎的临床疗效评价

目的：评价舌下特异性免疫治疗变应性鼻炎（allergicrhinitis,AR）的临床疗效,探讨提高AR疗效的治疗措施。方法：选择同期门诊及住院治疗的AR患者76例,在患者自愿的前提下,将患者分为对照组（n=40例）和观察组（n=36例）,对照组患者给予常规药物治疗措施,观察组患者在上述治疗措施的基础上加行舌下特异性免疫治疗,治疗12个月后比较两组患者变异性鼻炎症状评分、变异性鼻炎体征评分、临床疗效及不良反应的发生情况。结果：治疗前,两组患者变异性鼻炎症状评分与体征评分比较。差异均无统计学意义（P〉0．05）;治疗12个月后,两组患者变异性鼻炎症状评分与体征评分均较治疗前显著降低,差异具有统计学意义（P〈0．05）,且观察组患者变异性鼻炎症状评分与体征评分显著低于对照组,差异具有统计学意义（P〈0．05）。对照组和观察组的治疗总有效率分别为为87．5％和100．0％,差异具有统计学意义（P〈0．05）。此外,两组治疗期间不良反应的发生率比较差异无统计学意义（P〉0．05）。结论：舌下特异性免疫治疗治疗AR,其临床疗效确切且安全可靠,值得推广和深入研究。     

Immunological effects of sublingual immunotherapy: clinical efficacy is associated with modulation of programmed cell death ligand 1, IL-10, and IgG4

Sublingual immunotherapy (SLIT) is an alternate route of administration of allergen-specific immunotherapy with an improved safety profile; to clarify the immune mechanisms elicited by this therapy, we analyzed the clinical and immunologic effects of SLIT in patients with a clinical history of ragweed sensitization. To analyze possible difference among immunotherapeutic protocols, we also compared patients receiving preseasonal, seasonal, or prolonged sublingual therapy (≥ 3 y); patients receiving symptomatic therapy alone were enrolled as well in the study. Clinical and immunological parameters were measured twice in and out of the pollination period. Clinical benefits, as measured by the visual analog scale for symptoms and for use of drugs, were evident in all three groups of individuals receiving immunotherapy, but were significantly better in patients undergoing prolonged SLIT. Immunologically, SLIT resulted in increased IL-10 production, programmed cell death ligand 1 expression, and concentration of allergen-specific IgG4, as well as in the reduction of CD80 and CD86 expression and IL-4 production. SLIT, thus, is associated with modulation of programmed cell death ligand 1 expression and IL-10 synthesis and favors the production of allergen-specific IgG4. These effects are evident from the first pollen season, independently from therapeutic regimen (preseasonal or seasonal) even if a prolonged treatment is necessary to obtain full clinical efficacy. A more detailed understanding of the interaction of allergen and APCs within the oral mucosa will allow improved targeting of allergy vaccine.     

Specific IgE response to different grass pollen allergen components in children undergoing sublingual immunotherapy

ABSTRACT: BACKGROUND: Grass pollen is a major cause of respiratory allergy worldwide and contain a number of allergens, some of them (Phl p 1, Phl p 2, Phl p 5, and Phl 6 from Phleum pratense, and their homologous in other grasses) are known as major allergens. The administration of grass pollen extracts by immunotherapy generally induces an initial rise in specific immunoglobulin E (sIgE) production followed by a progressive decline during the treatment. Some studies reported that immunotherapy is able to induce a de novo sensitisation to allergen component previously unrecognized. METHODS: We investigated in 30 children (19 males and 11 females, mean age 11.3 years), 19 treated with sublingual immunotherapy (SLIT) by a 5-grass extract and 11 untreated, the sIgE and sIgG4 response to the different allergen components. RESULTS: Significant increases ( p < 0.001) were detected for Phl p 1, Phl p 2, Phl p 5, and Phl p 6, while sIgE levels induced in response to Phl p 7 and Phl p 12 were low or absent at baseline and unchanged following SLIT treatment; no new sensitisation was detected. As to IgG4, significant increases were found for Phl p2 and Phl p 5, while the increase for Phl p 12 was not significant. In the control group, no significant increase in sIgE for any single allergen component was found. CONCLUSIONS: These findings confirm that the initial phase of SLIT with a grass pollen extract enhances the sIgE synthesis and show that the sIgE response concerns the same allergen components which induce IgE reactivity during natural exposure.     

Fitness costs associated with Cry1Ac-resistant Helicoverpa zea (Lepidoptera: Noctuidae): a factor countering selection for resistance to Bt cotton?

The heritability, stability, and fitness costs in a Cry1Ac-resistant Helicoverpa zea (Boddie) (Lepidoptera: Noctuidae) colony (AR) were measured in the laboratory. In response to selection, heritability values for AR increased in generations 4-7 and decreased in generations 11-19. AR had significantly increased pupal mortality, a male-biased sex ratio, and lower mating success compared with the unselected parental strain (SC). AR males had significantly more mating costs compared with females. AR reared on untreated diet had significantly increased fitness costs compared with rearing on Cry1Ac treated diet. AR had significantly higher larval mortality, lower larval weight, longer larval developmental period, lower pupal weight, longer pupal duration, and higher number of morphologically abnormal adults compared with SC. Due to fitness costs after 27 generations of selection as described above, AR was crossed with a new susceptible colony (SC1), resulting in AR1. After just two generations of selection, AR1 exhibited significant fitness costs in larval mortality, pupal weight and morphologically abnormal adults compared with SC1. Cry1Ac-resistance was not stable in AR in the absence of selection. This study demonstrates that fitness costs are strongly linked with selecting for Cry1Ac resistance in H. zea in the laboratory, and fitness costs remain, and in some cases, even increase after selection pressure is removed. These results support the lack of success of selecting, and maintaining Cry1Ac-resistant populations of H. zea in the laboratory, and may help explain why field-evolved resistance has yet to be observed in this major pest of Bacillus thuringiensis cotton, Gossypium hirsutum L.     

Safety of sublingual immunotherapy

Sublingual immunotherapy (SLIT) is now recognized as a viable alternative to the classical injection route and it is currently used in everyday clinical practice in Europe. Sublingual administration is particularly attractive for children since it is completely pain-free. To date, no fatalities from SLIT have been reported, but two cases of anaphylaxis to inhalant allergens have been reported. The large majority of the adverse events reported in literature is described as mild. Most of them involve the mouth (burning or itching) or the gastrointestinal tract (stomachache, nausea) and usually self-resolve in a few days without any intervention. At present, SLIT represents the main option for allergists, however, tablet immunotherapy could become an interesting alternative to sublingual drops.     

Therapeutic efficacy of sequential therapy with OK-432, cyclophosphamide,IL2-cultured lymphocytes andin vivo IL2 against advanced murine plasmacytoma

BALB/c mice inoculated IP with a syngeneic plasmacytoma MOPC104E were treated with a combination of a streptococcal preparation, OK-432 (1 KE, 0.1 mg/mouse), low-dose of cyclophosphamide (CPA, 1 mg/kg) and adoptive transfer of tumor-bearer-spleen cells (2 x 10(7) cells) cultured with IL2 and sonicated tumor extract (adoptive immunotherapy; AIT). The consecutive protocol of OK-432 (day 8, 9 post inoculation) - CPA (day 10) - AIT (day 11) was the most effective. Rate of complete remission was highest when recombinant (r-) IL2 was injected to the mice after AIT. Moreover, another bacterial preparation, Nocardia rubra cell wall skeleton and another low-dose chemotherapy, Mitomycin C could be used successfully instead of OK-432 or CPA. Transfer test of intraperitoneal cells (tumor cells plus host cells) of mice on day 11 post inoculation (on the day of AIT) revealed that OK-432 augmented the susceptibility of peritoneal cells to cultured lymphocytes in inhibition of transplantability, and that CPA after OK-432 augmented the anti-tumor effect of tumor-bearer-spleen cells which act synergistically with cultured lymphocytes. This therapy schedule seems to be the best model to augment the effect of AIT with minimal side effect.