Sustained remission induced by 2 years of treatment with benralizumab in patients with severe eosinophilic asthma and nasal polyposis.

BACKGROUND AND OBJECTIVE: Several randomized controlled trials (RCTs) have shown that benralizumab is characterized by a good profile of efficacy and safety, thereby being potentially able to elicit clinical remission on-treatment of severe eosinophilic asthma (SEA). The main goal of this multicentre observational study was to verify the effectiveness of benralizumab in inducing a sustained remission on-treatment of SEA in patients with or without comorbid chronic rhinosinusitis with nasal polyps (CRSwNP). METHODS: Throughout 2 years of treatment with benralizumab, a four-component evaluation of sustained remission of SEA was performed, including the assessment of SEA exacerbations, use of oral corticosteroids (OCSs), symptom control and lung function. RESULTS: The present study recruited 164 patients suffering from SEA. After 24 months of add-on biological therapy with benralizumab, 69 (42.1%) achieved the important target of sustained remission on-treatment (exacerbation rate = 0, OCS dose = 0, pre-bronchodilator FEV1 ≥80% pred., ACT score ≥ 20). During the same period, a persistent improvement of CRSwNP (SNOT-22 < 30, NP recurrence = 0) was observed in 33 (40.2%) out of 82 subjects with concomitant NP. The latter comorbidity and post-bronchodilator reversibility of airflow limitation were two independent predictors of sustained remission on-treatment (OR = 2.32, p < 0.05 and OR = 5.59, p < 0.01, respectively). CONCLUSION: Taken together, the results of this real-life clinical investigation indicate that benralizumab can induce a sustained remission on-treatment of SEA, especially in those patients with comorbid CRSwNP and reversible airflow limitation.

Comparison of evidence of treatment effects in randomized and nonrandomized studies on allergen immunotherapy.

Nonrandomized studies (NRS) on allergen immunotherapy (AIT) particularly lend themselves to evaluate outcomes that are insufficiently addressed in randomized controlled studies (RCTs). However, NRS are prone to several sources of bias, which limit their validity. We aimed at comparing AIT effects between RCTs and NRS and evaluate the reasons for discrepancies in study results. In this analysis, we compared NRS on AIT (including subcutaneous and sublingual immunotherapy, SCIT and SLIT, respectively) with SLIT and SCIT RCTs from published meta-analyses, assessing the Risk of Bias (RoB) for each study and the certainty of evidence from NRS and RCTs using the GRADE approach. We found: (1) very serious RoB in the 7 NRS included in the meta-analysis showing a large difference between AIT and controls (standardized mean difference [SMD] for symptom score [SS], -1.77; 95% CI, -2.30, -1.24; p < .001; I2 = 95%) with very low certainty evidence; (2) serious RoB in the 13 SCIT-RCTs reporting a moderate-to-high difference between SCIT and controls (SMD for SS, -0.81; 95% CI, -1.12, -0.49; p < .001; I2 = 88%) with moderate certainty evidence; (3) low RoB in the 13 SLIT-RCTs reporting a small benefit (SMD for SS, -0.28; 95% CI, -0.37, -0.19; p < .001; I2 = 54.2%) with high certainty evidence. Similar results were reported for medication score. Our evidence is sufficient to conclude that the magnitude of effect estimates of NRS and RCTs directly correlate with the degree of RoB and inversely with the overall evidence certainty. NRS, which are more affected than RCTs by bias resulting in low certainty evidence, showed the largest effect size. Sound NRS are needed to complement RCTs.

Hypersensitivity reaction during enzyme replacement therapy in lysosomal storage disorders. A systematic review of desensitization strategies.

Lysosomal storage diseases (LSDs) are rare genetic metabolic disorders that cause the accumulation of glycosaminoglycans in lysosomes due to enzyme deficiency or reduced function. Enzyme replacement therapy (ERT) represents the gold standard treatment, but hypersensitivity reaction can occur resulting in treatment discontinuation. Thus, desensitization procedures for different culprit recombinant enzymes can be performed to restore ERT. We searched desensitization procedures performed in LSDs and focused on skin test results, protocols and premedication performed, and breakthrough reactions occurred during infusions. Fifty-two patients have been subjected to desensitization procedures successfully. Skin tests, with the culprit recombinant enzyme, deemed positive in 29 cases, doubtful in two cases, and not performed in four patients. Moreover, 29 of the 52 desensitization protocols used at the first infusion were breakthrough reaction free. Different desensitization strategies have proved safe and effective in restoring ERT in patients with previous hypersensitivity reactions. Most of these events seem to be Type I hypersensitivity reactions (IgE-mediated). Standardized in vivo and in vitro testing is necessary to better estimate the risk of the procedure and find the safest individualized desensitization protocol.

Use of a commercial feed supplement based on yeast products and microalgae with or without nucleotide addition in calves.

The use of feed additives with antioxidant and immune response modulatory activity could be a useful strategy in suckling calves to reduce morbidity and mortality. This strategy is based on several feed additives tested for these purposes. The aim of the paper is the examination of a commercial feed additive for adult cows for use in calves, with and without nucleotide supplementation. Seventy-five Holstein Friesian male calves were divided in 3 groups, with each calf randomly assigned to a group according to birth order. All calves received 2 L of pooled colostrum within 2 h of birth. The commercial feed supplement group was orally administered with 5 g/head of Decosel (dried brewer's yeast lysate (Saccharomyces cerevisiae), brewer's yeast walls (Saccharomyces cerevisiae), diatoms, spirulina, barley flour, calcium carbonate; Agroteam srl, Torrimpietra, Italy) and the nucleotides + commercial feed supplement group was orally administered with 5 g/head of an additive containing 2.5 g of Decosel and 2.5 g of nucleotides once daily from birth to 25 d. The control group was orally administered 20 mL of fresh water/head once daily. Calves that received the supplement and the nucleotides showed lower rates of protein and metabolizable energy conversion, with longer villi and greater crypt depth in duodenum. Moreover, the commercial feed supplement alone increased antioxidant capacity [2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) and ferric-reducing antioxidant power] in plasma some activity of antioxidant liver enzymes, and peripheral blood mononuclear cell viability after in vitro concanavalin A and H2O2 stimuli. Dietary supplementation with a commercial feed supplement containing yeast products (yeast cell walls and hydrolyzed yeast) and microalgae enhanced the redox balance and gut morphology in calves, allowing calves to improve their immune response, increasing resistance to stress. Moreover, these beneficial effects were strongly potentiated when dietary nucleotides were added to the supplement.

Effectiveness of benralizumab in severe eosinophilic asthma: Distinct sub-phenotypes of response identified by cluster analysis.

BACKGROUND: Benralizumab is effective in severe eosinophilic asthma (SEA), but suboptimal responses are observed in some patients. Although several factors have been associated with benralizumab response, no cluster analysis has yet been undertaken to identify different responsiveness sub-phenotypes. OBJECTIVE: To identify SEA sub-phenotypes with differential responsiveness to benralizumab. METHODS: One hundred and five patients diagnosed with SEA who had completed 6 months of benralizumab treatment were included in a hierarchical cluster analysis based on a set of clinical variables that can be easily collected in routine practice (age, age at disease onset, disease length, allergen sensitization status, blood eosinophil count, IgE levels, FEV1 % predicted, nasal polyposis, bronchiectasis). RESULTS: Four clusters were identified: Clusters 2 and 3 included patients with high levels of both IgE and eosinophils (type-2 biomarkers high), whereas Clusters 1 and 4 included patients with only one type-2 biomarker at a high level: IgE in Cluster 1 and eosinophils in Cluster 4. Clusters 2 and 3 (both type-2 biomarkers high) showed the highest response rate to benralizumab in terms of elimination of exacerbations (79% and 80% respectively) compared to Clusters 1 and 4 (52% and 60% respectively). When super-response (the absence of exacerbation without oral corticosteroid use) was assessed, Cluster 2, including patients with more preserved lung function than the other clusters, but comparable exacerbation rate, oral corticosteroid use and symptom severity, was the most responsive cluster (87.5% of patients). CONCLUSIONS: Our cluster analysis identified benralizumab differential response sub-phenotypes in SEA, with the potential of improving disease treatment and precision management.

Effectiveness and safety of dupilumab in patients with chronic rhinosinusitis with nasal polyps and associated comorbidities: a multicentric prospective study in real life.

BACKGROUND: Biologics are currently one of the main treatment options for a number of diseases. The IgG4 monoclonal antibody dupilumab targets the Interleukin-4 receptor alpha chain, thus preventing the biological effects of the cytokines IL-4 and IL-13, that are essential for the Th2 response. Several controlled trials showed that dupilumab is effective and safe in patients with atopic dermatitis (AD), severe asthma and chronic rhinosinusitis with nasal polyps (CRSwNP), thus resulting in approval by regulatory agencies. Aim of the study was to evaluate the efficacy and safety of dupilumab in adult patients with CRSwNP stratified by common overlapping comorbid conditions. METHODS: We performed a multicenter, observational, prospective study enrolling adult patients with severe CRSwNP who had started dupilumab treatment in the context of standard care from January 2021 to October 2021. Data were collected from twentynine Italian secondary care centers for allergy and clinical immunology, all of which were part of the Italian Society of Allergy, Asthma and Clinical Immunology (SIAAIC). A number of efficacy parameters were used. Patient data were compared using the Wilcoxon test for paired data. All statistical analyses were performed with SPSS version 20 (IBM, Armonk, NY, USA). RESULTS: In total, 82 patients with nasal polyposis were identified. A significant improvement was detected for all the applied efficacy parameters, i.e. 22-item Sino-Nasal Outcome Test (SNOT-22) and bilateral endoscopic nasal polyp score (NPS) scores for CRSwNP, Rhinitis Control Scoring System (RCSS) and Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) scores for allergic perennial rhinitis, Forced Expiratory Volume in the 1st second (FEV1) and Asthma Quality of Life Questionnaire (AQLQ) scores for asthma, Eczema Area and Severity Index (EASI) and Dermatology Life Quality Index (DLQI) scores for AD. A non-significant improvement was also obtained in the Urticaria Activity Score over 7 days (UAS7) for chronic spontaneous urticaria. Treatment with dupilumab was well tolerated. CONCLUSIONS: These data suggest that dupilumab treatment in patients suffering from CRSwNP and associated comorbidities may be suitable. Such outcome, although confirmation by trials is warranted, suggests the possibility to treat different disorders with a single therapy, with favorable effects especially under the cost-effectiveness aspect.

Benefits and Implications of Resveratrol Supplementation on Microbiota Modulations: A Systematic Review of the Literature.

Resveratrol is a polyphenol that has been shown to possess many applications in different fields of medicine. This systematic review has drawn attention to the axis between resveratrol and human microbiota, which plays a key role in maintaining an adequate immune response that can lead to different diseases when compromised. Resveratrol can also be an asset in new technologies, such as gene therapy. PubMed, Cochrane Library, Scopus, Web of Science, and Google Scholar were searched to find papers that matched our topic dating from 1 January 2017 up to 18 January 2022, with English-language restriction using the following Boolean keywords: ("resveratrol" AND "microbio*"). Eighteen studies were included as relevant papers matching the purpose of our investigation. Immune response, prevention of thrombotic complications, microbiota, gene therapy, and bone regeneration were retrieved as the main topics. The analyzed studies mostly involved resveratrol supplementation and its effects on human microbiota by trials in vitro, in vivo, and ex vivo. The beneficial activity of resveratrol is evident by analyzing the changes in the host's genetic expression and the gastrointestinal microbial community with its administration. The possibility of identifying individual microbial families may allow to tailor therapeutic plans with targeted polyphenolic diets when associated with microbial dysbiosis, such as inflammatory diseases of the gastrointestinal tract, degenerative diseases, tumors, obesity, diabetes, bone tissue regeneration, and metabolic syndrome.

Effectiveness of SARS-CoV-2 Vaccines for Short- and Long-Term Immunity: A General Overview for the Pandemic Contrast.

BACKGROUND: The recent COVID-19 pandemic produced a significant increase in cases and an emergency state was induced worldwide. The current knowledge about the COVID-19 disease concerning diagnoses, patient tracking, the treatment protocol, and vaccines provides a consistent contribution for the primary prevention of the viral infection and decreasing the severity of the SARS-CoV-2 disease. The aim of the present investigation was to produce a general overview about the current findings for the COVID-19 disease, SARS-CoV-2 interaction mechanisms with the host, therapies and vaccines' immunization findings. METHODS: A literature overview was produced in order to evaluate the state-of-art in SARS-CoV-2 diagnoses, prognoses, therapies, and prevention. RESULTS: Concerning to the interaction mechanisms with the host, the virus binds to target with its Spike proteins on its surface and uses it as an anchor. The Spike protein targets the ACE2 cell receptor and enters into the cells by using a special enzyme (TMPRSS2). Once the virion is quietly accommodated, it releases its RNA. Proteins and RNA are used in the Golgi apparatus to produce more viruses that are released. Concerning the therapies, different protocols have been developed in observance of the disease severity and comorbidity with a consistent reduction in the mortality rate. Currently, different vaccines are currently in phase IV but a remarkable difference in efficiency has been detected concerning the more recent SARS-CoV-2 variants. CONCLUSIONS: Among the many questions in this pandemic state, the one that recurs most is knowing why some people become more seriously ill than others who instead contract the infection as if it was a trivial flu. More studies are necessary to investigate the efficiency of the treatment protocols and vaccines for the more recent detected SARS-CoV-2 variant.

When there is no communication between urban planners and public health operators: urban Dermanyssus gallinae infestations in humans.

At the international level, it is necessary to apply urban health strategies that can integrate concrete actions to protect and promote health in urban and architectural planning. In cities, the "urban fauna" mostly consists of synanthropic birds (sparrows, starlings, swallows, martins, jackdaws, crows, hawks, gulls, pigeons) that have adapted to a continuous relationship with humans. These animals enrich the ecological network of biodiversity but also pose health problems. The most successful avian colonizers are pigeons (Columba livia), which proliferate due to the abundance of food available to them and the absence of predators. Pigeons may harbor several organisms that are pathogenic for humans, and among these the role of Dermanyssus gallinae should not be underestimated. In the absence of their preferred pigeon host, these mites will move from the nest to windowsills and window frames from which they attack humans. The Authors show that modern architectural design features in towns can favor the establishment and proliferation of pigeons, contributing to the public health risk for dermanyssosis or other diseases related to these birds. They describe an outbreak of dermanyssosis due to incorrect or unsuitable structural interventions, and highlight the need of re-thinking urban architectural choices in order to safeguard public health.

High levels of gut-homing immunoglobulin A+ B lymphocytes support the pathogenic role of intestinal mucosal hyperresponsiveness in immunoglobulin A nephropathy patients.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) is the most frequent primary glomerulonephritis. The role of the microbiota and mucosal immunity in the pathogenesis of IgAN remains a key element. To date, the hypothetical relationship between commensal bacteria, elevated tumour necrosis factor (TNF) superfamily member 13 [also known as B-cell activating factor (BAFF)] levels, perturbed homoeostasis of intestinal-activated B cells and intestinal IgA class switch has not been clearly shown in IgAN patients. METHODS: We studied the intestinal-renal axis connections, analysing levels of BAFF, TNF ligand superfamily member 13 (APRIL) and intestinal-activated B cells in IgAN patients, healthy subjects (HSs) and patients with non-IgA glomerulonephritides. RESULTS: IgAN patients had increased serum levels of BAFF cytokine, correlating with higher amounts of five specific microbiota metabolites, and high APRIL cytokine serum levels. We also found that subjects with IgAN have a higher level of circulating gut-homing (CCR9+ ß7 integrin+) regultory B cells, memory B cells and IgA+ memory B cells compared with HSs. Finally, we found that IgAN patients had high levels of both total plasmablasts (PBs) and intestinal-homing PBs. Interestingly, PBs significantly increased in IgAN but not in patients with other glomerulonephritides. CONCLUSIONS: Our results demonstrate a significant difference in the amount of intestinal-activated B lymphocytes between IgAN patients and HSs, confirming the hypothesis of the pathogenic role of intestinal mucosal hyperresponsiveness in IgAN. The intestinal-renal axis plays a crucial role in IgAN and several factors may contribute to its complex pathogenesis and provide an important area of research for novel targeted therapies to modulate progression of the disease.

Dupilumab elicits a favorable response in type-2 inflammatory comorbidities of severe atopic dermatitis.

BACKGROUND: This case is the first report describing rapid, successful treatment of severe atopic dermatitis (AD) and comorbid type-2 inflammatory diseases in the same patient, with dupilumab treatment, with no side-effects. CASE PRESENTATION: We report on effects of dupilumab in a patient with severe AD, a long-standing history of a mild, perennial allergic rhino-conjunctivitis, moderate asthma and chronic rhinosinusitis with nasal polyps (CRSwNP). CONCLUSIONS: Patients suffering from AD, asthma, allergic rhinitis and CRSwNP may be eligible for dupilumab single treatment that is possibly advantageous also from the pharmaco-economic standpoint.

The immunoglobulin γ marker 17 allotype and KIR/HLA genes prevent the development of chronic hepatitis B in humans.

Hepatitis B virus (HBV) infection causes a self-limiting disease in most individuals. However, < 10% of infected subjects develop a chronic disease. Genetic host variability of polymorphic genes at the interface of innate and acquired immunity, such as killer immunoglobulin-like receptors (KIR), their human leucocyte antigen (HLA) and IgG allotypes (GM), could explain this different clinical picture. We previously showed a protective role of the KIR2DL3 gene for the development of chronic hepatitis B (CHB), and a detrimental role of the KIR ligand groups, HLA-A-Bw4 and HLA-C2. We have expanded the previous analysis genotyping patients for GM23 and GM3/17 allotypes. The comparison of the patients with CHB with those who resolved HBV infection showed that the presence of GM17 allele virtually eliminated the risk of developing CHB (OR, 0·03; 95% CI, 0·004-0·16; P < 0·0001). In addition, the combination of GM17, KIR2DL3, HLA-A-Bw4 and HLA-C2 was highly sensitive to predict the outcome of HBV infection.

Cost-effectiveness of grass pollen allergen immunotherapy in adults.

BACKGROUND: Major scientific societies, such as the EAACI or the AAAAI, do not express any suggestion on which form of allergen immunotherapy (AIT) is to be preferred (subcutaneous immunotherapy, SCIT, vs sublingual immunotherapy, SLIT). This choice could depend on their relative pharmacoeconomic value. OBJECTIVE: To assess the cost-effectiveness of AIT for grass pollen, administered as SCIT or SLIT. METHODS: We created a Markovian Model, to evaluate, in a hypothetical cohort of adult patients suffering from moderate-to-severe rhino-conjunctivitis with or without allergic asthma, the cost-effectiveness of SLIT (tablets, Grazax® and Oralair® ) or SCIT (various currently available products, plus indirect nonmedical costs, such as travel and productivity costs) in addition to pharmacological therapy, assuming a 9-year horizon to capture AIT long-term effects. The incremental cost-effectiveness ratio (ICER) was calculated assuming pharmacological therapy as the reference comparator. RESULTS: In the base case, SCIT was slightly more expensive, but more effective than SLIT, being the most cost-effective option (ICER for SCIT, €11 418; ICER for SLIT, €15 212). ICERs greater than €120 000 for both SCIT and SLIT were demonstrated in a scenario assuming that low treatment persistence rates, which are common in real-life, lead to absence of long-term AIT clinical benefit. Considering indirect nonmedical costs SLIT resulted more cost-effective than SCIT (ICER for SCIT, €17 318; ICER for SLIT, €15 212). CONCLUSION: In daily practice, AIT for grass pollens may be a cost-effective option only in patients with low discontinuation rates. SCIT, which is less affected by this limitation than SLIT, seems the most cost-effective AIT form.

Efficacy of dupilumab in atopic comorbidities associated with moderate-to-severe adult atopic dermatitis.

BACKGROUND: Dupilumab is an anti-IL-4Rα antibody used in the treatment of patients with moderate-to-severe atopic dermatitis (msAD). This study explored the potential benefit of dupilumab in perennial allergic rhinoconjunctivitis (PAR) and perennial allergic asthma (PAA) caused by indoor allergens in adults with msAD. METHODS: This multicentric, prospective, observational, real-life study included adult patients with msAD who had been treated with dupilumab in 16 Italian care centres. Efficacy outcomes regarding AD, PAR and PAA were collected at baseline and 16 weeks. Safety was also assessed. RESULTS: We enrolled 123 patients with msAD. Between baseline and 16 weeks of treatment, the following measurements decreased statistically significantly: Eczema Area and Severity Index, SCOring AD, Patient-Oriented Eczema Measure, pruritus score, sleep score, Dermatology Life Quality Index and IgE. Dupilumab treatment in patients with comorbid PAR (n = 41) was associated with significant improvements in PAR disease control (measured using a Rhinitis Control Scoring System) and in PAR Quality of life (QoL) (measured using the Rhinoconjunctivitis QoL Questionnaire scores). In 32 patients with comorbid PAA, dupilumab significantly improved PAA control (measured using the Asthma Control Test and five-item Asthma Control Questionnaire scores) and disease-related QoL (measured using the Asthma QoL Questionnaire scores). Thirty-five patients (28.5%) developed conjunctivitis during the study period. CONCLUSION: These results support the benefits of dupilumab for adult patients with PAR and/or PAA associated with msAD.

Benralizumab improves patient reported outcomes and functional parameters in difficult-to-treat patients with severe asthma: Data from a real-life cohort.

In the last decade, an increasing number of randomized controlled trials (RCTs) on biologic therapy in patients with severe asthma have included patient-reported outcomes (PROs) as secondary efficacy measures. The majority of these RCTs showed a benefit in symptoms and quality of life. However, the magnitude of this benefit remains uncertain, because it rarely exceeded the minimal important difference (MID), owing to a significant improvement in the control group (placebo effect). Real-life studies on biologic therapies assessing PRO are scarce. They may support and integrate RCT results through their different experimental design. This real-life retrospective study provides data on 15 patients with difficult-to-treat severe eosinophilic asthma treated with benralizumab up to 6 months. Asthma quality of life questionnaire (AQLQ) and asthma control test (ACT) were assessed and administered at each visit to minimize the Hawthorne effect. Changes in general accepted efficacy measures, such as forced expiratory volume in 1 s (FEV1), peak expiratory flux (PEF), exacerbation rate and blood eosinophils, from baseline were also assessed. AQLQ and ACT improved from 3.9 ± 0.4 to 5.2 ± 0.4 and from 15.6 ± 5.7 to 18.1 ± 5.6, respectively. FEV1 increased of about 250 ml (+14%). PEF increased from 288 ± 107 to 333 ± 133 l/min. The number of exacerbations requiring OCS courses decreased from 2.8 ± 2.2 to 0.5 ± 0.8. Eosinophil counts dropped to 25.6 ± 15 cells/microliter. In conclusion, most patients reported improvements in AQLQ and ACT greater than MID, suggesting that these outcome represent a sensitive tool in real-life effectiveness studies. Our approach reduced the limitations of transition questions and the Hawthorne effect, increasing findings reliability.

Desensitization in Iron Product Allergy.

Iron deficiency is the main cause of anemia in both sexes, with women being more commonly affected. Iron therapy is currently considered an effective and safe remedy to replenish the iron storages. Iron can be administrated both orally and intravenously. In particular, intravenous (IV) iron therapy is widely used when oral iron preparations are either not tolerated or ineffective. Indeed, IV iron improves iron stores more rapidly. Two main immunological responses have been described for iron hypersensitivity reactions (HSRs): IgE-mediated allergy and complement activation-related pseudo-allergy. Here, we report 3 cases of adult patients with iron allergy, who were successfully treated with two different desensitization procedures, respectively. Analysis of these cases demonstrates that, in the presence of HSRs to iron products, desensitization is an effective and safe procedure that prevents treatment discontinuation and hence allows therapeutic target achievement.

Safety of measles, mumps, and rubella vaccine in egg allergy: in vivo and in vitro management.

BACKGROUND: Egg allergy is the second most prevalent form of food allergy in childhood. In spite of the evidence accumulated, inoculating egg allergy children with attenuated vaccines grown on chick embryo cell cultures, such as the measles, mumps, and rubella (MMR) vaccine, is regarded (erroneously) as potentially dangerous or even anaphylactogenic, by many. An issue perceived as particularly conflicting also by Health Professionals. CASE PRESENTATION: A 15-year-old boy, with a history of severe egg allergy in early infancy, who was still sensitized to egg allergens, including baked egg, had never received MMR vaccination, in fear of possible anaphylaxis, in spite of the fact that this vaccination is mandatory in the first year of life, in Italy. Because of that, he was not allowed to attend school, longer, and was referred to us in order to assess the potential risk of MMR vaccination. Upon thorough allergologic workup, sensitization to MMR vaccine components was excluded by an in vivo approach, consisting in skin prick tests, intradermal tests, and subcutaneous injection test, corroborated by vaccine-specific B-lymphocyte proliferation assay, ex vivo. T-cell proliferation in response to MMR vaccine was also excluded. Eventually, the boy was inoculated with MMR vaccine and was readmitted to school. CONCLUSIONS: The diagnostic strategy adopted appears feasible and easy-to-perform and may be adopted in controversial cases (as the one reported), characterized by previous severe allergic reactions to egg. The B-lymphocyte proliferation assay we developed may represent a useful and reliable tool not only in research but also in clinical practice.

Adult Renal Stem/Progenitor Cells Can Modulate T Regulatory Cells and Double Negative T Cells.

Adult Renal Stem/Progenitor Cells (ARPCs) have been recently identified in the human kidney and several studies show their active role in kidney repair processes during acute or chronic injury. However, little is known about their immunomodulatory properties and their capacity to regulate specific T cell subpopulations. We co-cultured ARPCs activated by triggering Toll-Like Receptor 2 (TLR2) with human peripheral blood mononuclear cells for 5 days and 15 days and studied their immunomodulatory capacity on T cell subpopulations. We found that activated-ARPCs were able to decrease T cell proliferation but did not affect CD8+ and CD4+ T cells. Instead, Tregs and CD3+ CD4- CD8- double-negative (DN) T cells decreased after 5 days and increased after 15 days of co-culture. In addition, we found that PAI1, MCP1, GM-CSF, and CXCL1 were significantly expressed by TLR2-activated ARPCs alone and were up-regulated in T cells co-cultured with activated ARPCs. The exogenous cocktail of cytokines was able to reproduce the immunomodulatory effects of the co-culture with activated ARPCs. These data showed that ARPCs can regulate immune response by inducing Tregs and DN T cells cell modulation, which are involved in the balance between immune tolerance and autoimmunity.

Maintenance-Phase Subcutaneous Immunotherapy with House Dust Mites Induces Cyclic Immunologic Effects.

BACKGROUND: Subcutaneous immunotherapy (SCIT) is an effective treatment of respiratory allergies including house dust mite (HDM) and Hymenoptera venom allergy. During the build-up phase, the allergen is administered weekly at increasing doses, while during the maintenance phase, it is administered at a fixed high dose every 4 weeks. Upon SCIT injection, the allergen is driven to the draining lymph nodes where it most likely induces an immune response. Immunologic changes are thus supposedly induced at each injection. OBJECTIVES: It is now established that SCIT induces tolerance in the long term, but the precise underlying immunologic mechanisms remain unclear. Therefore, we wanted to analyze the immunologic changes induced in both innate and adaptive immune cells at each individual SCIT administration during the maintenance phase in HDM-allergic patients. More specifically, we wondered whether the changes in regulatory T cell (Treg) and IgE+ B cell percentages, which are observed at the end of a 3-year course of SCIT, already occurred during the maintenance phase and whether these possible changes were sustained. METHODS: We enrolled 6 patients suffering from HDM allergic rhinitis and undergoing maintenance HDM SCIT for 18-24 months. The same SCIT extract was used for all patients. We collected blood samples at 5 time points: T1 (immediately before a given SCIT injection), T2 (9 days after T1), T3 (29 days after T1 and right before the successive administration), T4 (39 days after T1), and T5 (61 days after T1 and just before the next injection). Six non-allergic age-matched healthy individuals were used as controls. Using flow cytometry, we assessed the following cell subsets in peripheral blood mononuclear cells: CD4 and CD8 T cells, Tregs, B cells, IgE+ B cells, NK and NKT cells, and total and activated basophils. RESULTS: HDM-allergic patients displayed increased percentages of CD4 and CD8 T cells and NK cells compared to healthy controls. In contrast, NKT cells, total B cells, and basophils were diminished. These differences were maintained throughout the time course and seemed to be independent of the periodical SCIT injections. On the contrary, Treg percentages were significantly reduced in all HDM-allergic patients at T1. However, they increased at T2 and T4 (9 days after each SCIT injection) but decreased again at T3 and T5, just before the next one, resulting in cyclic changes. IgE+ B cells were significantly increased at T1, even more increased after each administration (T2, T4), and went back to their initial levels at T3 and T5, also resulting in a cyclic pattern. CONCLUSIONS: Our data suggest that during the SCIT maintenance phase, cycles of expansion/contraction of Tregs and IgE+ B cells occur at each SCIT injection. Therefore, the sustained induction of immune tolerance by SCIT, through the increase of Tregs, seems to depend on the periodical exposure to the allergen, at least during the early steady state.

Immunological characterization of onion (Allium cepa) allergy.

INTRODUCTION: Onion (Allium cepa) handling can induce contact dermatitis, rhinoconjunctivitis and asthma. However, only sporadic reports exist on allergic reactions to onion consumption. AIM: We describe herein a case of a 35-year-old man who had an episode of anaphylaxis following cooked onion ingestion. We evaluated onion-specific IgE, the possible cross-reactivity between onion and peach and lymphocyte proliferation in response to onion. MATERIAL AND METHODS: Specific IgE was evaluated using two techniques: skin test and ImmunoCAP technology. Cross-reactivity between onion and peach was evaluated by IgE-ELISA inhibition test. As for lymphocyte proliferation, blood mononuclear cells were stained with CFSE dye and cultured with an in-house onion extract. Proliferation and phenotype was assessed by flow-cytometry. RESULTS: The skin test and ImmunoCAP confirmed the IgE-dependent response towards onion. The incubation of the patient serum with increasing concentrations of the peach extract reduced only scarcely (~30%) onion-specific IgE. Interestingly, B cells but not T cells showed proliferation in response to onion extract. CONCLUSIONS: In conclusion, our report shows that cooked onion can induce severe allergic reactions, suggesting the presence of thermostable components. Moreover, we applied for the first time a B-cell-based approach to the diagnosis of food allergy. This latter approach might also be applied to other allergic conditions.