Food tolerance and other mysteries

In a timely review and opinion article this month, Berin and Mayer take up the issue of therapeutic induction of food tolerance (J Allergy Clin Immunol 2013;131:14-22). They put to the reader the question of whether we truly understand the mechanisms that restore natural tolerance or induce tolerance in sensitized individuals, noting that without this knowledge it will not be possible to achieve tolerance through therapy in the majority of food allergic patients.

Berin and Mayer begin with a concise review of current understanding about how the human body achieves self and non-self tolerance. They cover central tolerance and peripheral tolerance induction in the thymus and gut, respectively, the development and function of natural and induced regulatory T cells, and anti-specific T-cell deletion and anergy in the context of establishing and maintaining peripheral tolerance. Immunologic profiles of critical immune cells and cytokines is also addressed.

The authors proceed with the question “is food allergy a defective T_reg response?” They review and summarize the current knowledge about T helper cell profiles in food allergic subjects and normal controls, nothing that T_reg frequencies were similar between the controls and the allergic subjects. Mouse models of food allergy are also presented.

Next, the question of whether tolerance can be induced in food allergic patients is discussed. The authors define tolerance as sustained non-responsiveness to a food allergen after therapy is discontinued, distinguishing it from desensitization that is achieved during therapy. Berin and Mayer review the research to date on immunotherapy for food allergy, noting the frequency of spontaneous tolerance. They point out that there has been little in the way of mechanistic findings that would demonstrate what immune regulatory mechanisms were operative between those who achieved desensitization and those who achieved tolerance. It remains unclear if tolerance is achieved by induction of T_reg or by decreased potency of allergic sensitization.

Berin and Mayer conclude by offering considerations for future research, such as novel routes of administration, allergen modification, the addition of adjuvants to enhance the immunotherapy, and manipulation of gut flora. Of particular importance, they press for genetic profiling of immune tolerance that develops naturally or therapeutically in order to design new methods for achieving tolerance in the majority of food allergic patients.

 

Re-equilibrating human health

Susan Prescott, PhD, MD makes a compelling case for broadly focused, interdisciplinary approaches to inflammatory non-communicable chronic diseases (iNCD) in her Current Perspectives contribution this month (JAllergy Clin Immunol 2013;131:23-30). She points to the global rise in allergies, obesity, cardiovascular disease and autoimmune diseases and their common characteristic of low grade chronic inflammation while discussing the radical and health-hostile environmental conditions that are known to influence these disease processes. Prescott states that the rise in allergic diseases specifically implicates vulnerability of the human immune system to micro- and global environmental shifts.

The author briefly discusses evidence that supports early immune dysfunction in infants and notes that environmental influences begin in utero. Thus, maternal health is a critical starting point to any preventive measures, such as dietary and nutritional support. She comments further on the need to create and sustain optimal immune development as a prerequisite to minimizing future causes of low grade chronic inflammation, which increases the risk associated with iNCD.

Prescott covers current research on important nutritional supplements known to impact immune function, such as fish oil, probiotics, and dietary soluble fiber, as well as the critical role of exposure to sunlight. She goes on to briefly discuss the roles of genetics, epigenetic modification and genetic plasticity in the context of adaptive and maladaptive evolutionary shifts.

Prescott concludes by urging interdisciplinary approaches to modifying the environment and a return to more traditional dietary and lifestyle patterns known to achieve and/or restore human health.

 

Standardizing research food challenges

A pressing need for standards of conduct for research-related double-blind, placebo-controlled, oral food challenges (OFC) provided the impetus for a consensus report by Sampson et al in this month’s issue (J Allergy Clin Immunol 2012;130:1260-1274).

After a brief review of the historical literature on diagnosing food allergy, Sampson et al present topical discussion summaries for major issues in the conduct of research OFC, noting that the guidance and recommendations apply equally to clinically performed challenges. The authors emphasize that patient/subject safety was the pre-eminent consideration. The following are highlights from their discussions:

·      Pre-challenge assessments. The authors cover important evaluations and practices prior to conducting OFC. These include case history, current food avoidance, comorbid conditions that impact safety such as atopic dermatitis and chronic disease, the utility of surrogate test results and their intrinsic problems, and the requirement for an optimal challenge setting. They also discuss the issue of differential severity of allergens as an important safety consideration prior to OFC.

·      Challenge procedures and assessments. Sampson et al discuss dosing schedules and their necessary variability tied to outcomes. General recommendations for dosing include low starting doses, separate active and placebo challenge days, dosing intervals no less than 20 minutes and appropriate, low fat matrices. Recording important, objective clinical parameters, such as respiratory symptoms and other physical reactivity symptoms, is covered. Sampson et al emphasize that scoring and stopping criteria must be pre-specified in light of the critical role of clinical judgment in OFC conduct. Delayed reaction considerations and subjective symptom issues are also reported. Tables of their recommendations are provided for reference.

·      OFC analysis and reporting. To ensure a reliable evidence base, Sampson et al provide guidance and recommendations for statistical analysis and reporting results, particularly from randomized trials. 

Revisiting LABAs with the help of Macbeth

Szefler and Busse provide an entertaining and thoughtful editorial this month on the predicament of LABA step-down by invoking Macbeth’s notorious witches’ ominous chant (J Allergy Clin Immunol 2012;130:1256-1259). Likening the clinician’s dilemma at the FDA recommendation to withdraw LABAs for safety reasons from treatment of well-controlled asthma to the troubling brew of the witches, the authors review the history of long-acting beta 2 agonists’ use and the evidence that supports the safety concerns that prompted the FDA’s action. Szefler and Busse note that a recent evidence review does not concur that LABAs are unsafe when used in combination with ICS and, in fact, concludes that withdrawal of LABAs in that treatment context results in asthma worsening.

At the heart of the controversy are several “Catch-22s”: how and when to step down and, critically, with what to replace LABAs if control is lost. Clinicians and researchers are concerned that the delay in safety reporting will also delay the development of new asthma drugs in the LABA category. Further, the FDA safety trial does not address how to step-down LABAs in the event of a poor safety profile. This would require yet another set of trials, which implies further delays.

Results from the current FDA-mandated safety study are expected to be reported in 2016. Until then, the authors provide approaches for possible step-down in patients on ICS and LABA combination products. Among these, they suggest that clinicians consider the asthma natural history, especially over the previous year, the possibility of adjusting either the ICS or the LABA, and alternative supportive treatments, such as omalizumab or tiotropium, if they decide to step-down the LABA. Szefler and Busse emphasize that there is no current evidence that supports changing the current EPR-3 guidelines, which already advise against LABA monotherapy.

A wart compendium: HPV infections in immunodeficiency diseases

November’s issue features an article from two NIAID researchers, Jennifer Leiding, MD and Steven Holland, MD, who present an inventory of HPV infections associated with primary immunodeficiencies (J Allergy Clin Immunol 2012;130:1030-1048). A short review of HPV immunopathology and epidemiology opens the authors’ discussions of the associated diseases and syndromes.

Beginning with those illnesses with which HPV infection is a predominant clinical presentation, Leiding and Holland present concise information on the symptomatic features, immunogenetic context and treatment approaches of the most common HPV-susceptible immunodeficiencies:

·      EV (epidermodysplasia verruciformis) is characterized by increased susceptibility to cutaneous HPV infection and associated with recurrent, pathological infection and malignant conversion. Autosomal recessive mutations in the genes EVER1 & 2, which code for transmembrane proteins thought to restrict HPV intracellular ingress, result in deficiency that raises HPV susceptibility across many immune cell types. HPV infection in EV is highly resistant to therapies.

·      WHIM (warts, hypogammaglobulinemia, infection and myelokathexis) syndrome, an autosomal dominant immunodeficiency, presents with pulmonary, gastrointestinal, and cutaneous infections and neutropenia. Dysplastic and malignant warts are the characteristic features. A gain-of-function mutation of the chemokine receptor CXCR4 results in impaired myeloid and dendritic cell signaling that permits greater HPV infection. Patients have good response to IVIg and bone marrow growth factors.

·      DOCK8 (dedicator of cytokinesis 8) deficiency is one of the combined immunodeficiencies in which infection by HPV and herpetic viruses are chronic and comorbid. Presentation is similar to STAT3-associated hyper-IgE syndrome.

Leiding and Holland also cover rare immunodeficiencies, such as idiopathic CD4 lymphopenia, severe combined immunodeficiency disease, GATA2 deficiency, Wiskott-Aldrich syndrome and Netherton syndrome, with which there have been a few reports of HPV infection. The authors provide an excellent table summarizing the immunodeficiency diseases that have associated HPV infection. Leiding and Holland wrap up noting that physicians should suspect immunodeficiency in their patients with recurrent, pervasive, and/or treatment refractory HPV infections.

Says first author Jennifer Leiding, from the National Institute of Allergy and Infectious Diseases: “Investigation of patients with susceptibility to HPV will lead to further understanding of host defense toward viruses as well as cutaneous and systemic immunity.”

Modeling asthma-related utilization

In the current socioeconomic climate, evaluating healthcare utilization in the context of chronic disease outcomes and intervention is vital. Think Framingham. Wu et al. in this month’s issue (J Allergy Clin Immunol 2012;130:1065-1070) step up to this challenge for asthma, designing and testing a prediction model that draws on data from the Childhood Asthma Management Program (CAMP). The authors use data on changes in prebronchodilator FEV₁ % predicted in subjects treated with ICS to simulate prediction of hospitalization, ED visits, and oral CS therapy associated with exacerbations. The simulated results are then compared with the actual data from CAMP to assess the model’s reliability.

Wu et al. report remarkable consistency between the simulation predictions and the CAMP data. As one example, their model predicted a 48% decrease in hospitalizations with ICS therapy compared to placebo. The observed decrease in the CAMP data was 49%. The authors comment that further testing with data not involved in developing the model is required and they invite other asthma investigators to collaborate. 

The allergenicity of “hypoallergenic” dogs

It’s a primitive social urge in humans to interact with dogs. So much so that many people found to be clinically sensitive to dogs will own them anyway. In this context, it is not surprising that the search for dogs that elicit a minimal allergic response would claim so much energy, but are there such things as “hypoallergenic” dogs? Vredegoor et al. look at that question in this month’s issue (J Allergy Clin Immunol 2012;130:904-909.e7).

The authors examine levels of the primary dog allergen, Can f 1, in samples from dog fur and skin, and settled and airborne dust from “hypoallergenic” dogs (Labradoodles, Poodles, Spanish water dogs, and Airedale terriers), normal allergenic dogs (Labrador retrievers), and a variety of breeds and mixed breeds that made up the control group. Their results are paradoxical and even ironic.

Poodles and Labradoodles had the highest levels of Can f 1 in their coat and skin; Labrador retrievers had the lowest. Hair and dander shedding was highest from Airedale terriers. Vredegoor et al. report that environmental levels of Can f 1 were not significantly different between “hypoallergenic” dogs and their allergenic counterparts, though homes with covered floors had overall lower environmental levels than homes with exposed floors. The authors note that other identified canine allergens, such as Can f 2 and 3, were not screened due to lack of available methods for analyzing large sample sizes. 

The authors also collected information from owners by administering questionnaires. Dog-allergic owners reported much fewer symptoms with the breeds thought to be hypoallergenic and did not report having different house-cleaning practices than non-allergic owners. It was noted that recent swimming by the dogs had an overall effect of lowering allergen levels and Vredegoor et al. speculated that this could contribute to the lower levels found in Labrador retrievers, which are frequent swimmers.

Vredegoor et al. conclude that there is no evidence that supports the label “hypoallergenic” with respect to dogs, so we asked the authors to comment on a possible explanation for the number of dog-allergic owners who reported experiencing fewer symptoms with certain dogs: Senior author Esmeralda J.M. Seegers-Krop replies, “We believe the health effects can be a kind of placebo effect in these people. It has been seen in cat allergic people as well (they report not to be allergic to their own cat but only to other cats).”

Asthma therapies targeting Il-13

This month’s clinical review article by Ingram and Kraft (J Allergy Clin Immunol 2012;130: 829-842) presents exhaustive and timely coverage of a complex issue in asthma treatment, namely, the interface of IL-13 pathophysiology, asthma phenotypes, and IL-13 targeted therapies. The authors take the discussion to foundations of IL-4/IL-13 signaling in asthma before delving into the clinical and investigative implications associated with IL-13 dominance in atopic asthma. The review comprehensively covers current knowledge on the clinical and genetic heterogeneity of asthma, emerging phenotypes and subtypes, biomarker diagnostics, and systemic and targeted therapy responses in well-characterized asthma phenotypes.


Review highlights include:

• Cluster analysis of clinical asthma phenotypes by several research groups, including the consistent finding of eosinophilic, high TH2 cytokine profile asthma and non-eosinophilic, low TH2 cytokine profile asthma.

• Evidence confirming therapeutic efficacy of systemic and targeted therapies in eosinophilic, high TH2 asthma.

• Reports of the successful use of biomarkers in characterizing response to therapy, including recent research involving omalizumab, mepolizumab, and lebrikizumab for patients with severe and/or uncontrolled asthma characterized using clinical and biomarker indices.

• Specific evidence for applying FENO, induced sputum, IgE, and periostin to treatment decision making.

Ingram and Kraft note that traditional and targeted therapies are effective only for eosinophilic, TH2 high asthma patients, leaving a gap in our knowledge about how to effectively manage the low TH2 profile patients. They also remark that TH2 inflammation in asthma patients may be more effectively assessed through the use of combinations of inflammatory and molecular markers, rather than relying on observations of single biomarkers. They conclude by commenting that application of the molecular features of asthma phenotypes, in combination with clinical evidence, is being used to predict response to intervention. They follow by pointing out that the current knowledge base has defined a gap in managing asthma that does not present with a TH2 dominant signature.

A collaborative model for drug development for rare diseases

This month’s issue holds an article by Fiorentino et al. putting forward a model for rare disease drug development and the first realization of this model (J Allergy Clin Immunol 2012;130:613-616). Fiorentino and colleagues at the FDA in CDER’s Division of Gastroenterology and Inborn Error Products chose the rare disease eosinophilic esophagitis (EoE) as the focus of their efforts to establish this new paradigm.

Noting the rise in prevalence and incidence of EoE, the authors discuss the knowledge gaps that create obstacles to effective clinical interventions. They use this information to construct their model of “rational” drug development, which includes defining the disease in clinical, research and sociocultural terms, evaluating the natural history of the disease using the definitions identified, and reliably assessing clinical and patient-reported outcomes.

Fiorentino et al. describe their efforts to date implementing this model. They tapped critical research groups, such as The International Gastrointestinal Eosinophil Researchers (TIGERs), North American Society of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) to open discussions on disease definition and urge the inclusion of disease and patient advocacy groups in this early process. Advocacy groups are identified as critical to the success of the model because they bring strong interest in the long-term success of research into the disease.

Early progress is reported for the determination of a functional disease definition and appropriate terminology. The authors note that findings from graduate student research supported by the EoE project demonstrate that inconsistent and vague terminology is impeding research efforts. Additionally, they comment that research is underway to understand the relationship between positive clinical outcomes and the esophageal mucosal eosinophilia that is diagnostic for EoE. They point out that there is a pressing need to define and characterize the EoE patient population in order to develop appropriate patient-reported outcome measures.

An editorial in this issue by Rothenberg et al. presents additional perspectives and considerations (pp#). Dr. Rothenberg notes that an upcoming meeting (Sept. 19) provides an opportunity for more information and exchange of opinion about the subject. For further information: https://www.signup4.net/public/ap.aspx?EID=20123759E&OID=50

A large cohort analysis of allergic outcomes from peanut and tree nut consumption during pregnancy

Current research has challenged the conventional wisdom of dietary avoidance of food allergens during pregnancy. A recent study from the UK found that avoidance of peanuts, specifically, during pregnancy did not confer significant protection from peanut allergy to the infant. Accordingly, the UK removed that recommendation. In the US, avoidance is only recommended for children at risk by heredity.

In this issue, Maslova et al. (J Allergy Clin Immunol 2012;130:724-732) from Center for Fetal Programming, Statens Serum Institut, present important results from an analysis of a very large Danish birth cohort (n=61,908). The authors look at development of asthma, wheeze, and allergic rhinitis – not food allergy – in children whose mothers consumed peanuts and tree nuts during pregnancy as compared to children whose mothers avoided these foods.

At 18 months, children whose mothers ate peanuts more than once a week were less likely to have parent-reported asthma, while children whose mothers ate tree nuts were less likely to report asthma, wheeze and recurrent wheeze. At 7 years, children of mothers who ate peanuts and/or tree nuts were less likely to have a registered diagnosis of asthma. These results all reached statistical significance. The association of tree nut consumption during pregnancy with decreased likelihood of self-reported allergic rhinitis during the first 7 years of life was borderline statistically significant.

Maslova et al conclude by suggesting that their results do not support avoidance or decreased consumption of peanuts and tree nuts during pregnancy. 

Secretory phenotype of mast cells localized in nasal polyps from chronic rhinosinusitis subjects

Takabayashi et al. present novel findings in this issue on the distribution and protease secretion of mast cells (MC) found in nasal polyps from subjects with chronic rhinosinusitis (CRSwNP) (J Allergy Clin Immunol 2012; 130:410-420.e5). The authors compared MC from the epithelium, glands, and submucosa of CRSwNP with uncinate biopsy tissue (UT) from subjects with CRS without nasal polyps (CRSsNP) and control subjects.

They found mast cells numbers were highly increased in NP epithelium and glands, in particular, as compared to UT from CRSsNP and control subjects. Further, the MC populations in NP were distinguishable on the basis of their protease profile. Mast cells from the NP epithelium were tryptase-carboxypeptidase A3 (CPA3)-positive/chymase-negative, while MC from NP glands were tryptase-CPA3-chymase-positive.


The authors note clear expansion in MC numbers that they suggest could be the result of increased migration and accumulation as well as proliferation. Since mast cell tryptase can activate protease-activated receptor (PAR) 2, which facilitates allergic inflammation, and mast cell chymase can activate PAR-1 signaling and is a potent glandular secretagogue, the results of Takabayashi et al suggest that mast cells localized in submucosal glands may be well positioned to drive important features of the inflammatory response associated with chronic rhinosinusitis and nasal polyp formation.

Association between traditional farming and childhood wheeze from the GABRIEL Advanced Study Group

The European GABRIEL Advanced Studies project has provided a large body of data and samples for investigating effects of traditional farm environments on childhood asthma and atopy. Research on the GABRIELA cohort has demonstrated that traditional farming environments like those found in Europe have a protective effect on childhood atopy and, less consistently, childhood asthma. Yet, recent findings show that microbial diversity in farming environments appears to play a stronger role for asthma than for atopy. This month’s issue holds another important report on the impact of farm life on different childhood wheeze phenotypes by Fuchs et al. (J Allergy Clin Immunol 2012;130:382-388.e6).

Fuchs et al note that there are different wheeze phenotypes that correlate to different clinical outcomes, and that comorbid atopy complicates the search for wheeze-specific farm effects. To address this, the authors partition the study population into atopic and non-atopic children. In addition to analyzing the farm effect on atopy, they further investigate the effect on different wheeze phenotypes (transient, current, persistent, late-onset), airway inflammation and lung function for atopic and non-atopic children, separately.

They report that farm environment has a significant beneficial effect on all wheeze phenotypes. This protective effect was independent of atopic sensitization. This was different for lung mechanics as measured by lung function and on airway inflammation, on which farming had no appreciable overall effect. However, farm-exposed atopic children had less severe lung function impairment and lower exhaled nitric oxide (FeNO) than non-exposed atopic children.

Fuchs et al. speculate that farming’s protective effects are mediated through antiviral activities of the innate immune system that minimize respiratory infections. Future steps in their research to better elucidate underlying mechanisms will be analyses in prospective setups and studies further including the analysis of innate and adaptive immune mechanisms related to defense against viral infections and the role of the microbiome in upper and lower airways herein.

Anti-IL17 mAb shows promising results in psoriasis treatment

Exciting – and surprising – results from a clinical trial for psoriasis are presented in this month’s issue by Krueger et al (J Allergy Clin Immunol 2012;130:145-154.e9). The authors report on a randomized trial of a new humanized IgG₄ monoclonal antibody, ixekizumab. It would be fair to say the results from their phase I trial are near astonishing.

Based on published evidence that psoriasis is a T_H17-mediated disease, the authors postulate that IL-17 acts as a “gatekeeping” cytokine in the pathogenesis of psoriasis, noting that much of the evidence from animal studies points to IL-22. They point out that IL-22 in humans is produced from a different T cell subset, T_H22 cells, unlike mice where T_H17 cell produce both.

Their speculation paid off. Krueger et al. report dose-dependent, significant improvement in both pathophysiology and clinical presentation of psoriasis subjects after only 2 weeks of ixekizumab treatment. Skin biopsies from subjects demonstrated rapid improvements in keratinocyte proliferation, hyperplasia, epidermal thickness, T cell and dendritic cell infiltration of the dermis and significantly suppressed expression of innate immunity peptides. After 6 weeks of treatment, the authors report that subjects’ skin appeared normal. Interestingly, 100% of subjects in the 150mg dosing group no longer presented clinically with psoriasis at 6 weeks of therapy. Krueger et al. comment that the effectiveness of ixekizumab at 2 and 6 weeks was surprising since other antibody therapies typically require 12 weeks to demonstrate efficacy. They also note that the adverse effects profile is agreeable and the drug well-tolerated.

Noting that many genes associated with psoriasis are co-regulated by IL-17 and TNF-α, Krueger et al. show that IL-17 blockade with ixekizumab is far more effective in suppressing the co-regulated genes than TNF-α blockade by etanercept. They suggest that their evidence shows that IL-17 is a pivotal cytokine in the pathology of psoriasis, affecting many effector functions of other T cell subsets.  

Immunomodulation of allergic disease by nematode infection

The consistent observation that developing countries have very low frequencies of atopy and allergic diseases has been correlated with environmental exposure to helminth infection. The hygiene hypothesis has been proffered to account for these observations as it has to explain protective effects of living on traditional farms. Small numbers of pilot and proof-of-concept trials have been looking at the nematode-allergy connection as possible therapy for a number of diseases.

This month’s issue presents a review by Jouvin and Kinet (J Allergy Clin Immunol 2012;130:3-10) of this pioneering research and the preliminary results that suggest that certain helminths may be human symbionts rather than parasites.

Jouvin and Kinet begin with an overview of current research into nematode therapy for inflammatory bowel and autoimmune diseases, employing Trichurus suis ova (TSO), or pig whipworm, to treat patients with Crohn’s Disease (CD), ulcerative colitis (UC) and multiple sclerosis (MS). The trials were very small, from 4 subjects to 54 subjects, with safety and tolerability as the endpoints.  There were no AEs reported in the CD and UC trials, and mild GI distress and transient eosinophilia in the MS trial that resolved without subjects dropping out from the studies. Stool specimens collected were all negative for ova and parasites, except an isolated sample in the MS trial. These limited safety results were sufficient for FDA to approve an open-label efficacy study of TSO in MS.

Jouvin and Kinet review the basics of the hygiene hypothesis and discuss the epidemiological and animal evidence for immunomodulatory effects of helminths, as well as limited results of helminth treatment in Western countries. The authors also cover the logic supporting the choice of TSO, in particular because it is not a known human pathogen.

They summarize the safety findings of published research and note their own experience with TSO in the treatment of peanut or tree nut allergy, which was consistent with other reports of transient, mild GI side effects and eosinophilia. Secondary efficacy reports are also included, with some preliminary findings being promising: in a study of CD, 70% of subjects attained remission at the end of the study; in a UC trial, 43% in the treatment group had improved disease compared to 17% in the control group; and in an MS study, a  lower rate of appearance of new lesions imaged by MRI was observed during active treatment. The authors also present an interesting single case report on nematode treatment for autism.

Jouvin and Kinet discuss the potential of other nematodes as therapeutic agents then review the biochemistry of helminth extracts, noting that a phosphorylcholine glycoprotein, ES-62, has been isolated as an effector molecule. They comment that ES-62 prevent mast cell activation and modulate T_H17 responses. Also, ES-62 has been shown to require TLR4 for its activity.

The authors conclude that TSO as seen from very preliminary data is safe and well tolerated, and limited data suggests it ameliorates certain autoimmune diseases. They urge continued research on the mechanisms and optimal dosing to achieve immunomodulation. 

Back to beginnings of farming for answers to protection against allergies and atopy

On behalf of the GABRIEL Advanced Studies Group supported by the European Commission, Illi et al. (J Allergy Clin Immunol 2012;129:1470-1477) provide their results from a survey study designed to address the high variability in reported protective effects associated with farm environments on asthma and allergies (pp#). The study group survey was structured into two phases with questions in phase II targeting exposure to specific elements of the farm environment. Farms were placed in one of three categories depending on farm activities and husbandry: farms with no dairy cows or cattle, but other farm animals, and grain cultivation, farms with dairy cows and/or cattle, but no grain cultivation, and finally, farms with dairy cows and/or cattle, and grain cultivation. Survey queries covered exposure in utero to 3 years.

Illi et al. report that protective effects were highest and most broad for children raised on farms with both cows and cattle and agriculture activities. Exposure to cows, cows’ milk and straw had the greatest protective effect for asthma, exposure to fodder storage and manure were most protective on atopic dermatitis. Interestingly, the data collected could not sufficiently account for the protective effect against hay fever and atopic sensitization. Overall single exposure effect was greatest with cows’ milk, which greatly reduced the risk of asthma, hay fever and atopic sensitization. Exposure to straw had the strongest association with asthma protection, though the authors noted that the effects of individual constituents and contaminants in straw, such as manure, grass pollen, and microbial elements, could not be separated out.

Illi et al. comment that protective associations supported different physiological pathways, noting that cow exposure was associated with respiratory disease protection and cows’ milk association with atopic sensitization pointed to gut-mediated immune development.

The authors conclude that traditional farming environments like those established in humankind’s first non-nomadic lifestyle are the most beneficial from an immunologic natural history perspective. This can account for the variability in farm environment results since farming practices diverge greatly between the US and Central Europe. 

A new category of rhinitis based on localized atopy

This month, Rondón et al. (J Allergy Clin Immunol 2012;129:1460-1467) present an important classificatory revision centered on their identification of a new rhinitis phenotype: local allergic rhinitis (LAR). Building on their previous research, the authors characterize LAR as local specific IgE (sIgE), T_H2 local tissue response, and positive nasal allergen provocation test (NAPT) results in the absence of clinical indicators of systemic atopy, such as positive skin tests and serum specific-IgE. Patients with LAR are known to respond positively to nasal corticosteroids. In addition, they note that conjunctivitis and/or asthma can be comorbid with LAR.

Rondón et al. effectively argue that the current allergic versus non-allergic rhinitis (AR and NAR, respectively) distinction is not sufficient in light of the findings of localized atopy. They suggest that patients diagnosed with idiopathic rhinitis or non-allergic rhinitis with eosinophilia may in fact have LAR, which would decisively impact clinical management as patients with true idiopathic or non-allergic (vasomotor) rhinitis would not respond to therapy like LAR patients would.

The authors propose a revised rhinitis classification (Table 1, pp#) that splits allergic rhinitis into systemic and local atopy subcategories. They estimate prevalence from European data to be between 47-62% of patients reporting seasonal or perennial allergy symptoms. Their and other early results have shown that house dust mite, grass, and olive pollen are common triggers, though they note that comprehensive findings are needed to refine NAPT specificity.

Rondón et al. review the published pathophysiology evidence as well as the reported clinical presentation. They clearly identify the gaps that future research should fill, such as clinical management overlap between AR and LAR, the need for more practical NAPT testing procedures, the relationship between LAR and atopic march, and mechanisms of localized allergic responses. The authors comment that patients with LAR receiving subcutaneous immunotherapy have increased tolerance upon repeat NAPT and also develop positive skin tests and detectable serum specific-IgE. 

The iatrogenic effect of successful ICS therapy on the progress of asthma research

This month’s issue features an editorial by Jeffrey Drazen, MD (J Allergy Clin Immunol 2012;129:1200-1201). Dr. Drazen presents the intriguing argument that our success in treating asthma with inhaled corticosteroids (ICS) has hampered significantly our ability to discern the complex, heterogeneous pathophysiology of the disease.

He briefly reviews for the reader the lengthy history of medicine’s attempts to understand and classify asthma, with reference to the JACI's 2011-2012 Asthma: Current Status and Future Directions series, which featured contributions from leaders in the field of asthma on topics such as asthma’s natural history and clinical presentation, gaps in diagnosis and treatment response, and new targets for therapy based on asthma genotypes. Dr. Drazen commends the efforts that have been made over the years, but notes that for all the research that’s been done, little true progress in early detection and prevention has resulted.

His argument is predicated on the observation that ICS efficacy for treating the inflammatory component of asthma is not specific to a single pathway and, thus, doesn’t inform the mechanisms of asthma biology. Notable work on anti-cytokine therapies for asthma is discussed, with the observation that its success has been less than expected. Drazen comments that these trials have demonstrated sensitive subgroups, but there are limited diagnostics available to identify them.

With a nod to a point raised in Stephen Holgate’s article in the JACI series (J Allergy Clin Immunol 2011;128:495-505), Dr. Drazen supports the idea that the immune dysfunction theory of asthma may need to be discarded in favor of focus on structural abnormality fundamental to the epithelium.

Drazen concludes by deflecting the idea that ICS therapy is the perfect treatment precisely because asthma is so heterogenous. He insists that understanding the specifics of asthma pathology and targeting those elements directly is the patient-centered mandate.

Three injections and counting...

Senti et al. have “injected” new hope into allergy immunotherapy (IT) with this month's report of the results of their research into intralymphatic administration of cat dander allergen for treatment of cat allergy (J Allergy Clin Immunol 2012;129:1290-1296). 

Conventional IT has a low appeal for most allergy sufferers because of the lengthy time requirement to achieve desensitization/tolerance. This is true for subcutaneous as well as sublingual IT. Although this treatment duration can be shortened by higher doses of allergen per treatment, the authors point out that this significantly increases risk of systemic reaction.

Senti et al. generated a unique delivery platform for the cat allergen, Fel d 1, using an HIV-derived translocation peptide combined with part of a human invariant chain that permitted targeting of the vaccine to the MHC class II pathway, avoiding phagocytosis and subsequent degradation. They report that the modular vehicle, MAT-Fel d 1, induced less in vitro degranulation of basophils and of mast cells in skin tests, suggesting that the vaccine may be safer than administration of unmodified allergen.

Subjects in the study received three inguinal intralymphatic injections of sequentially increased doses of MAT-Fel d 1 or placebo under ultrasound guidance. Subjects received injections once every 4 weeks. At 5 weeks after the 3^rd injection, subjects in the treatment group had 5-fold increased levels of IgG₄ compared to controls. This was positively correlated to increased titers of IL-10. The authors report nasal tolerance increased in the treatment group by a factor of 74 compared to the control group. Senti et al. also report increased tolerance of skin prick testing and intradermal testing.  At day 300 follow up, the treatment group reported continued nasal and ocular tolerance.

In conclusion, Senti et al. emphasize the rapid achievement of increased tolerance with a greater safety profile of their modular vaccine, MAT-Fel d 1. They note the need for larger studies permitting increased statistical power as well as efficacy assessment by symptom and medication reduction. 

[Update 5/2/12] We asked Dr. Senti and senior author Thomas Kündig to comment on the next steps in their research. They note, "[We] are currently planning a dose escalation and phase IIb study for further clinical development. Also, MAT molecules containing major bee venom allergen Api m 1, and dust mite allergens and birch allergens have been generated and work well in mice."

Protective effect shown in infants at risk for atopy treated with bacterial lysate

Lau et al. (J Allergy Clin Immunol 2012;129:1040-1047) report their findings from a controlled trial of heat-inactivated bacterial lysate treatment in infants with inherited risk of atopy in this month’s issue. Citing proof-of-concept research and epidemiological reports on lowered atopy incidence in rural populations, the authors hypothesize that intentional exposure to heat-inactivated bacteria might confer protection from atopy. Their study included infants with one or both parents with a history of atopic disease (allergic rhinitis, eczema, asthma or combination).

Infants were treated orally with heat-killed Echerichia coli and Enterococcus faecalis lysate for 7 months, then followed until age 3 years. The primary outcome was the presence or absence of atopic dermatitis (AD) at the end of treatment. At 31 weeks, only 10% of treated infants with single parent risk developed AD compared to 19% of infants treated with placebo. The effect was even greater in infants with paternal atopy only. Treatment effect was strongest in infants with a single parent with allergic rhinitis. No effect was observed for infants with allergic asthma, AD, or combination.

Though Lau et al. measured gut flora during the treatment period, there was no measurable alteration in flora that could be attributed to treatment. Additionally, total serum IgE levels did not differ between the two groups. The authors conclude that their study shows a possible differential atopy risk associated with paternal heredity.